Randall Kimple, MD, PhD

Randall Kimple, MD, PhD

Associate Professor

Department of Human Oncology

I am an associate professor in the Department of Human Oncology with a clinical practice and research laboratory. In my clinical practice, I specialize in treating patients with malignancies of the head and neck. I am a member of the UW Multidisciplinary Head and Neck Program and work closely with head and neck surgeons, medical oncologists, radiologists, speech and swallow therapists and other specialists to best meet the individual patient’s needs.

The goal of my lab is to improve the care of cancer patients through translational cancer research while providing a supportive world-class learning environment for scientists at all levels and from all backgrounds. We pursue this goal by studying the molecular mechanisms underlying the response to radiation and the development of therapeutic resistance in head and neck and lung cancer and by developing approaches to treat side effects of radiation therapy. We utilize cellular and mouse models that we have developed including patient-derived xenografts and intrinsic resistance models to understand therapeutic response.

In addition to my clinical and research roles, I teach undergraduate, graduate and medical students as well as residents and postdoctoral fellows. I try to give these students a sense of the breadth of opportunities in medicine and challenge them to be the best doctors and scientists they can be. I encourage my students to come to the clinic with me so that they can see cancer from our patient’s perspective.

Education

Postdoctoral Fellow, University of Wisconsin–Madison, Tumor Virology (2012)

Postdoctoral Fellow, University of North Carolina at Chapel Hill, Cancer Biology (2010)

Resident, University of North Carolina at Chapel Hill, Radiation Oncology (2010)

Intern, University of North Carolina at Chapel Hill, Internal Medicine (2006)

MD, University of North Carolina at Chapel Hill, Medicine (2005)

PhD, University of North Carolina at Chapel Hill, Pharmacology (2003)

BS, Michigan State University, Environmental Science and Management (1998)

Academic Appointments

Associate Professor, Human Oncology (2018)

Assistant Professor, Human Oncology (2012)

Assistant Professor, Medical Physics (2014)

Selected Honors and Awards

Association of Residents in Radiation Oncology Teacher of Year Award (2017)

University of Wisconsin Postdoctoral Mentor Award (2017)

Medical Faculty Award, University of North Carolina (2005)

Lineberger Comprehensive Cancer Center Graduate Fellow Award (2002)

Outstanding Senior Award, Michigan State University (1998)

College of Natural Science Convocation Speaker, Michigan State University (1998)

Tower Guard Sophomore Honor Service Society, Michigan State University (1995-1996)

Boards, Advisory Committees and Professional Organizations

American Society for Pharmacology and Experimental Therapeutics (2003-pres.)

Radiological Society of North America (2006-pres.)

American Society for Radiation Oncology (2006-pres.)

American Society for Clinical Oncology (2006-pres.)

University of Wisconsin Institute for Clinical and Translational Research (2010-pres.)

Radiation Research Society (2012-pres.)

American Society of Clinical Oncology Leadership Development Program (2017-2018)

Co-chair, Big Ten Cancer Research Consortium Head and Neck Working Group (2017-pres.)

ASTRO Annual Meeting Scientific Track co-chair – Biology (2017-2022.)

International Journal of Radiation Oncology Biology and Physics, Senior Associate Editor (2014-2020)

International Journal of Radiation Oncology Biology and Physics, Critical Reviews Editor (2021-pres.)

Research Focus

Head & Neck Cancer

Kimple Lab member Memorial Union Terrace
Kimple Lab member Memorial Union Terrace: (left to right) Shrey Ramesh, Lindsey Abel, Yong-Syu(Aaron) Lee, Cristina Paz, Michael Luy, Sammy Bradley, Zafer Gurel, and Randy Kimple.
In the Kimple Lab we seek to improve the care of cancer patients through our strengths in translational radiation research while providing a supportive, world-class learning environment for scientists at all levels.

Radiation therapy can be used to cure many cancer patients. We use powerful patient-derived model systems to study how cancers evolute to overcome current treatments and study treatments to overcome radiation-induced toxicity to improve the quality of life of our patients. Our long-term goal is to offer personalized treatments to each patient.

Patient derived xenografts

We have established one of the largest tissue repositories of head and neck cancer patient-derived xenografts and have helped define best practices for the establishment, passage, and use of these valuable resources. Patient derived xenografts are established in mice directly from patient biopsies and are thought to better represent the biology of their human source than model cell lines grown in plastic tissue culture plates. Current work seeks to understand how the decisions we make when we establish these models influences their use as personal avatars and drives tumor evolution. We use single-cell approaches to study changes in the tumor’s gene expression, genome, and proteome. In addition, we are beginning to utilize “humanized” models in which the mouse host has a functional immune system. This would allow us to use this resource to study immunotherapy and immunomodulation.

In addition to our focus on head and neck cancer models, we have also established PDXs from brain metastases in lung cancer patients, pancreas cancer, melanoma, breast cancer, and from rare tumors such as adenoid cystic carcinoma and NUT midline carcinomas. We have used our PDXs to partner with several pharmaceutical companies to test novel drugs in head and neck cancers. Please contact us if you have interest in this aspect of our work.

Establishing Patient-Derived Xenografts (PDX)

Funding:

  1. NCI R37 (2021-2026)

Relevant publications:

https://pubmed.ncbi.nlm.nih.gov/?term=Kimple+RJ+and+%28PDX+or+tumorgraft%29&sort=date

Therapy-Induced Autophagy and Therapy Resistance

Autophagy, or self-eating, is a pro-survival process cells use to recycle damaged parts during times of stress. Autophagy is often activated during nutrient deprivation, although many types of cell stress can activate autophagy. We are interested in how head and neck cancer cells use autophagy to respond to radiation and chemotherapy. Autophagy is activated in a dose and time dependent manner by radiation and the epidermal growth factor receptor (EGFR) inhibitor, cetuximab. A grant funded by the American Cancer Society seeks to understand the molecular mechanisms by which radiation and cetuximab activate autophagy. In addition, we will test drugs that specifically block autophagy to determine whether they can increase sensitivity to anticancer treatments.

diagram of autophagy

diagram of autophagy

Cancer cells feature a high degree of plasticity, allowing them to adapt rapidly changing tumor microenvironment through metabolic reprogramming. Cancer cell plasticity, with genetic and epigenetic alterations, promote the diversity of cancer cells and contributes to heterogeneity within the tumor. With this in mind, tumors harbor cells with a wide genetic and metabolic heterogeneity, including cancer stem cells. Thus, a combination of target-specific agents might be required to effectively prevent the development of radio/drug-resistance to eliminate tumor cells entirely. In this manner, we developed a multimodal approach to overcome the potential cellular plasticity and heterogeneity within HNC tumors. Our current studies in this area are aimed at targeting the ROS scavenger system and lactate metabolism in malignancies using rationally developed combination treatments.

Funding

  • American Cancer Society Research Scholar Grant
  • American Cancer Society Mission Boost Grant

Relevant Publications

https://pubmed.ncbi.nlm.nih.gov/?term=Kimple+RJ+and+%28autophagy%29&sort=date

Cell therapies for radiation toxicity

Radiation-induced xerostomia (RIX) represents one of the most common long-term side effects seen in patients who receive radiotherapy to the head and neck. Head and neck cancer (HNC) accounts for nearly 4% of cancers within the United States, estimates show that over 60,000 new cases with occur in 2021. Most HNC treatments include radiation therapy (RT), chemotherapy, targeted therapy, surgery, or a combination of treatments. RT is a primary treatment modality in HNC, while effective in treating cancer, RT causes auxiliary damage to surrounding normal tissues. Xerostomia is a subjective condition of dry mouth hallmarked by decreased saliva production and/or alterations in the composition of saliva. Radiation impairs the saliva-producing acinar cells along with inducing functional changes in the salivary gland ultimately leading to xerostomia. RIX adversely affects quality of life in patients, aside from the general discomfort of dry mouth, patients experience increased dental carries, alterations in taste, fissures in and around the mouth, difficulty swallowing, chewing, and speaking. Currently, there are no available treatment options that address the causes of xerostomia, existing options for patients suffering from RIX are either palliative or accompanied by harsh side effects. There is a critical need to develop safe and effective therapies for RIX. Emerging preclinical and clinical research suggests administration of mesenchymal stromal cells (MSC) to the radiation-damaged salivary gland can lead to increased saliva production and rescue of glandular structures. While it has been demonstrated that MSCs benefit the radiation-damaged salivary gland there is little showing the mechanisms behind MSC function within the gland. The goal of my project is to elucidate how MSCs benefit the radiation-damaged salivary gland in a murine model. Ultimately, the identification of a mechanism will lead to the development of novel, effective, and safe treatment option for RIX.

diagram of dry mouth in head and neck cancer patients

Funding

  • NIH/NIDCR UG3 DE030431

Relevant publications

Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease

Human papillomavirus related head and neck cancer

Human papillomavirus (HPV) is a ubiquitous virus that can cause multiple cancers in humans. Our lab studies HPV-related head and neck cancer and has helped define the molecular basis for the improved outcomes in patients with HPV-related head and neck cancer (in comparison to HPV-unrelated). Multiple clinical trials investigating how we can personalize treatment for patients based on the cause of their cancer are now ongoing. The role the HPV oncogenes E6 and E7 play in how these cancers respond to treatment is a common theme across the research in the Kimple Lab.

Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review
From Swick et al. Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review. https://www.ncbi.nlm.nih.gov/pubmed/26049691

Relevant Publications

https://pubmed.ncbi.nlm.nih.gov/?term=Kimple+RJ+and+%28HPV+or+human+papillomavirus%29&sort=date

Kimple Lab members on stairs
Kimple Lab member (top left to bottom): Cristina Paz, Shrey Ramesh, Michael Luy, Zafer Gurel, Sammy Bradley, Yong-Syu (Aaron) Lee, Lindsey Abel, Qianyun (Lexi) Luo, Kwang Nickel, Annie Glassey, and Randy Kimple.

Current Team Members

Principal Investigator

Randall Kimple, MD PhD

Dr. Kimple received his MD, PhD and completed residency in radiation oncology at the University of North Carolina. He is a member of the Multidisciplinary Head and Neck Oncology team and leads a group of talented researchers seeking to improve the care of patients with head and neck cancer.

Kwang P Nickel, PhD
Research Scientist

Dr. Nickel received her PhD. in Nutritional Science at Purdue University. She has been a member of the Kimple Lab since 2012.

She has been involved in various projects including the establishment of Head and Neck PDXs and the investigation of chemo and radiation responses in both in vivo and in vitro HNC models. Her current focus of the study is to characterize the radiobiological effects of different radiation sources such as 137Cs, 60Co, and X-ray. Due to the worldwide radioactive 137Cs irradiator replacement program to the non-radioactive alternative of X-ray irradiation, there is a need to compare these radiation sources for biological effectiveness in both cell culture and animal models since X-ray produces a significantly different energy spectrum compared to 137Cs irradiation.

 Zafer Gurel, PhD
Research Scientist

Dr. Gurel received his PhD at the University of Istanbul in Biophysics and has been member of the Kimple Lab since 2019.

Lindsey Abel, BS
Research Specialist

Ms. Abel completed her BS at the University of Arkansas and has been a member of the Kimple Lab since 2017. She works closely with the UW Head and Neck Cancer SPORE team.

Yong-Syu “Aaron” Lee
Graduate Student, CBMS program (https://www.vetmed.wisc.edu/education/ms-phd/)

Mr. Lee is pursuing a PhD with his work focused on the role of therapy induced autophagy in resistance to chemotherapy and radiation.

Cristina Paz
Graduate Student, Cancer Biology Program, SciMed GRS, Voice Research Training Program

https://scimedgrs.wisc.edu/

https://cancerbiology.wisc.edu/

https://www.surgery.wisc.edu/education-training/training-for-researchers/voice-research-training-program/

Ms. Paz is pursuing a PhD with her work focused on the use of mesenchymal stromal cells for the treatment of radiation induced xerostomia (dry mouth).

Graduate Students

Past / Current Trainee Name Undergrad, Predoc, postdoc Training period,

Awards during training

Prior Academic Degree(s), Year, Institution Title of Research Project Source of Support in Kimple Lab/Position after leaving Kimple Lab
Past Robert Yang Pre, Univ of Wisconsin 2010 – 2012 BS/BA

2007

University of Wisconsin

Establishment of primary tumor xenografts from head and neck cancer Resident

Otolaryngology

University of Minnesota

Minneapolis, MN

Past Julian Hong Pre, Univ of Wisconsin 2010 – 2014 BS, 2008

MS, 2009

Stanford University

Patterns of radiation oncology practice in the longitudinal oncology registry of head and neck carcinoma (LORHAN®) study Resident

Radiation Oncology

Duke University

Durham, NC

Past Tyler Fowler Pre, Univ of Wisconsin

Co-mentor with Bryan Bednarz

2011 – 2015

2011 – Advanced opportunity fellowship graduate research scholar

2011 – Biological Science Scholar

2013 – 4th Annual Standard Imaging Travel Award. American Association of Physicists in Medicine Annual Meeting

2013 – igus Young Engineer’s Support Program Award

BS, 2011 Southern Oregon University Development and biovalidation of a high-throughput microirradiator for the study of autophagy in head and neck cancer Resident in Medical Physics

Stanford University

Palo Alto, CA

Past Andy Stein Pre, Univ of Wisconsin 2013-2015

Graduation with Research Honors

2013-2014 Shapiro Fellowship

BS, 2009 Washington University Molecular markers of response in head and neck cancer xenografts Resident

Otolaryngology

Case Western Reserve University School of Medicine

Cleveland, OH

Past Stephanie Rice Pre, Univ of Wisconsin 2013-2014

Graduation with Research Honors

BS, 2007

UW Lacrosse

Skin cancers of the head and neck. Resident

Radiation Oncology

University of Maryland

Baltimore, MD

Past Evan Liang Pre, Univ of Wisconsin 2014-2017

2014 Shapiro Summer Research Fellow

BS, 2012

Harvard University

Outcomes in Merkel Cell Carcinoma Resident

Radiation Oncology

Wayne State University

Past Leonard Che Fru Pre, Univ of Wisconsin, co-mentor with Larry DeWerd 2013-2019 BS 2008 Minnesota State Univ

MS, 2012 Minnesota State Univ

Measurement of hemoglobin oxygen saturation in tissue with an optical device Resident in Medical Physics

University of Wisconsin

Madison, WI

Current Yong-Syu (Aaron) Lee Pre, Univ of Wisconsin 2017-pres BS, 2008 China Medical University, Taichung Taiwan

MS, 2010 National Yang-Ming University, Taipei Taiwan

Therapy induced autophagy in head and neck cancer American Cancer Society grant (Kimple PI)
Current Cristina Paz Pre, Univ of Wisconsin, Cancer Biology 2019-pres

2020- pres UW T32 Voice Training Grant

BS, 2013 Northeastern Illinois University, MS, 2015 Case Western Reserve University Mesenchymal Stromal Cell therapy for treatment of radiation induced xerostomia Voice disorders training grant

      Postdoctoral Fellows

Past / Current Trainee Name Undergrad, Predoc, postdoc Training period,

Awards during training

Prior Academic Degree(s), Year, Institution Title of Research Project Source of Support in Kimple Lab/Position after leaving Kimple Lab
Past HaoShun Huang Postdoc, Univ of Wisconsin 2012 – 2013 PhD, 2012, Univ of Wisconsin Genomic and therapeutic characterization of primary tumor xenografts from head and neck cancer Medical Science Liaison, Sanofi
Past Adam Swick Postdoc, Univ of Wisconsin 2013 – 2017

2015 AACR Scholar in Training Travel Award

2015 PhRMA Foundation Translational Science Postdoctoral Fellow

PhD, 2013, Univ of Wisconsin Molecular targeting of head and neck cancer to overcome therapeutic resistance Project Manager, Catalent
Past John Floberg Postdoc, Univ of Wisconsin 2013-2014 PhD, 2012, Univ of Wisconsin Correlation of FDG-PET with response in oropharyngeal cancers. Resident in Radiation Oncology, Washington University in St Louis
Past Anirban Chatterjee Postdoc, Univ of Wisconsin 2015-2017 PhD, 2014, Univ of Calcutta Head and Neck Cancer Stem Cells Assistant Professor

Bolpur College, University of Burdwan, Bolpur, Birbhum, West Bengal, India

Past Jaimee Eckers Postdoc, Univ of Wisconsin 2016-2018 PhD, 2013, Univ of Iowa Autophagy in head and neck cancer Assistant Professor

Nevada State College

Henderson, NV

 

 

 

      Medical Residents/Fellows

Past / Current Trainee Name Training period,

Awards during training

Prior Academic Degree(s), Year, Institution Title of Research Project Position after leaving Kimple Lab or Current Position
Past Stephen Rosenberg 2014-18 MD, 2013, Rutgers Readability of online patient information Assistant Professor

H. Lee Moffit Cancer Center

Tampa, FL

Past H. Cindy Ko 2015-19 MD, 2014, New York University Mindfulness meditation to reduce physician burnout Kaiser Permanente of Southern California, Los Angeles, CA
Current Grace Blitzer 2018-present

2020 RSNA Research Resident Award

2021 ASCO Young Investigator Award

MD, 2017, Medical College of Wisconsin Treatments for radiation induced xerostomia Resident, Radiation Oncology, University of Wisconsin
Current Charles Gast 2020-present MD PhD, Oregon Health & Science University Treatments for radiation induced xerostomia Resident, Otolaryngology, University of Wisconsin

 

 

      Other Trainees

Past / Current Trainee Name Undergrad, Predoc, postdoc Training period,

Awards during training

Prior Academic Degree(s), Year, Institution Title of Research Project Current Position/Source of Support
Past Holly Edwards Undergrad, Univ of North Carolina 2006-2007 DNA damage modulation by HER4 in breast cancer Pediatric resident at Palmetto Health Children’s Hospital, Columbia, SC
Past Jill Zartman Undergrad, Univ of North Carolina 2008-2010 Nutritional needs assessment in radiation oncology clinics Service Member at FoodCorps
Past Christopher Harris Predoc, Univ of North Carolina 2008-2010 BS

2007

East Carolina University

Validation of pazopanib as a lung cancer radiosensitizer Psychiatry Resident US Navy
Past Timothy Baerg Undergrad, Univ of Wisconsin 2011-2012

·  2011 UW Undergraduate Research Scholar

Assessment of apoptosis in head and neck cancer after radiation Medical Student (MD/MBA)

University of Michigan

Ann Arbor, MI

Past Molly Smith Undergrad, Univ of Wisconsin 2010 – 2013

·  2012 AACR Undergraduate Poster Competition 3rd Place Award

Cell cycle differences in HPV-positive and HPV-negative head and neck cancer Graduate student

Cancer Biology

University of Cincinnati

Cincinnati, OH

Past Grace Blitzer Undergrad, Univ of Wisconsin 2010 – 2013

·  2011 UW Hilldale Undergraduate Research Fellow

·  2012-13 AACR Thomas J. Bardos Science Education Award for Undergraduate Students

·  2012 Senior Honors Thesis Grant

·  2013 University Book Store Academic Excellence Award

Radiation and chemotherapy response profiles of HPV-positive head and neck cancer Medical student

Medical College of Wisconsin

Milwaukee, WI

Past Kai Ludwig Undergrad, Univ of Wisconsin 2012 – 2013 Autophagy in head and neck cancer Graduate student

Department of Medical Physics

University of Wisconsin

Madison, WI

Past Alexandra Torres Pre, Univ of Wisconsin 2012 – 2013

2012 – Advanced opportunity fellowship graduate research scholar

2013 – Virology Training Grant

BS, 2011 Harvard University HPV regulation of EGFR expression Graduate Student

Cancer Biology Training Program

Department of Oncology

University of Wisconsin

Madison, WI

UW Advanced opportunity fellowship, Virology Training Grant

Past Ebony Carson Undergrad, Univ of Wisconsin 2012 – 2016

2012 UW Undergraduate Research Scholar

Effect of p53 reactivation in HPV-positive head and neck cancer. Clinical Research Coordinator

Medical College of Wisconsin

Milwaukee, WI

Past Divya Bhat Undergrad, Univ of Wisconsin 2012 – 2016

2012 UW Undergraduate Research Scholar

Generation of HPV-16 E6 mutant cell lines. Graduate student, University of Iowa, Iowa City, IA
Past Dana Gunderson Undergrad, Univ of Wisconsin 2013 –  2015 Characterization of radiation response in a new HPV-positive HNC cell line. Dental School,

Marquette University

Milwaukee, WI

Past Ali Bailey Undergrad, Univ of Wisconsin 2013 – 2015

2015 AACR Undergraduate Poster Competition Honorable Mention

Autophagy in Head and Neck cancer Medical Student

Loyola University

Chicago, IL

Past Michael Fisher Undergrad, Univ of Wisconsin 2014 – 2017

2016 UW Hilldale Undergraduate Research Fellow

Effects of HPV oncoprotein mutation on head and neck cancer radiation sensitivity Medical Student

University of Chicago

Chicago, IL

Past Prashanth Prabakaran Predoc, Univ of Wisconsin 2015-2016 BS, University of Wisconsin Molecular targeting of Adenoid Cystic Carcinoma Medical Student

University of Wisconsin

Madison, WI

Past Aastha Pandey Undergrad, Univ of Wisconsin Summer 2015 – high school

2015 Science Research Internship Program

2016 – 2020

Radiosensitization of bladder cancer Undergraduate

University of Wisconsin

Madison, WI

Past Justin Skiba Undergrad, Univ of Wisconsin 2015 – 2019 Autophagy in head and neck cancer Medical Student

University of Pittsburgh

Pittsburgh, PA

Past Margot Miller Undergrad, Univ of Wisconsin 2015 – 2019

2018 UW Hilldale Undergraduate Research Fellow

2019 David Boren Scholar

2019 Lauguage Flagship Scholar

Dual targeting of EGFR and MTORC in HNC Russian Flagship Program, Almaty, Kazakhstan
Past Amal Javaid Predoc, Univ of Wisconsin 2016 – 2018 BS, University of Wisconsin Radiosentiziation of adenoid cystic carcinoma Medical Student

University of Pittsburgh

Pittsburgh, PA

Past Austin Maas Predoc, Univ of Wisconsin 2016 – 2018 BS, University of Michigan Head and neck cancer initiating cells Medical Student

University of Michigan

Ann Arbor, MI

Past Gopika Senthikumar Undergrad, Univ of Wisconsin 2016 – 2019

2018 UW Hilldale Undergraduate Research Fellow

Autophagy in head and neck cancer MD PhD Student

Medical College of Wisconsin

Milwaukee, WI

Past Amber Bo Undergrad, Univ of Wisconsin 2017 – 2019 AXL in head and neck cancer Medical Student

Medical College of Wisconsin

Milwaukee, WI

Past Ashley Kromke Undergrad, Univ of Wisconsin 2018 – 2021 FGFR in lung cancer Undergraduate

University of Wisconsin

Madison, WI

Current Samantha Bradley Undergrad, Univ of Wisconsin 2019 – pres

2020 UW Sophomore Research Award

2021 UW Hilldale Undergraduate Research Fellowship

Autophagy in head and neck cancer Undergraduate

University of Wisconsin

Madison, WI

Past Haley VanBeek Undergrad, Univ of Wisconsin 2019 – 2021 ATM inhibition in lung cancer Medical Student

Medical College of Wisconsin

Milwaukee, WI

Current Lexi Luo Undergrad, Univ of Wisconsin 2018 – pres

2021 Goldwater Fellowship

2021 Biochemistry Research Award

2021 UW Hilldale Undergraduate Research Fellowship

2021 Astronaut Foundation Scholar

Metabolic alterations to increase sensitivity to radiation in head and neck cancer Undergraduate

University of Wisconsin

Madison, WI

Past Mitchell Boettner Undergrad, Univ of Wisconsin 2019 – 2020 Autophagy in head and neck cancer Undergraduate

University of Wisconsin

Madison, WI

Current Annie Glassey Undergrad, Univ of Wisconsin 2020 –

2021 UW Hilldale Undergraduate Research Fellowship

Cell therapy to prevent and treat radiation induced xerostomia Undergraduate

University of Wisconsin

Madison, WI

Current Shrey Ramesh Undergrad, Univ of Wisconsin 2021-

2021 UW Sophomore Research Award

RBE determination of electronic brachytherapy sources Undergraduate

University of Wisconsin

Madison, WI

Current Michael Luy Undergrad, Univ of Wisconsin 2019- Metabolic alterations to increase sensitivity to radiation in head and neck cancer Undergraduate University of Wisconsin

Madison, WI

Album

Poster presentation

Rachel Orbuch, Adam Swick and Austin Maas at AACR meeting

Kimple lab in front of Senator Johnson's office in Washington, DC

Locations

University Hospitals and Clinics

Clinical trials

I play an active role in the UW Head and Neck Cancer Disease Oriented Team which oversees and prioritizes head and neck cancer focused clinical research activities at the University of Wisconsin. In addition, I am co-chair of the Big Ten Cancer Research Consortium Head and Neck Cancer Working Group. This group focuses on early phase multi-institutional clinical trials for patients with head and neck cancers.

Through clinical trials I hope to bring promising treatments to patients and integrate advanced imaging, novel molecular tests, and molecular markers to match each patient to the right treatment for their individual cancer.

Relevant Publications

https://pubmed.ncbi.nlm.nih.gov/?term=Kimple+RJ+and+%28IRB+OR+Review%29&sort=date

Kimple group shot in front of White House

In addition to my clinical and research roles, I teach undergraduate, graduate and medical students as well as residents and postdoctoral fellows. I try to give these students a sense of the breadth of opportunities in medicine and challenge them to be the best doctors and scientists they can be. I encourage my students to come to the clinic with me so that they can see cancer from our patient’s perspective.

I serve as Faculty Director of the Graduate Program in Clinical Investigation https://ictr.wisc.edu/graduate-program-in-clinical-investigation/ which is an applied degree program in which trainees focus on the creation of novel methodologies and tools for translational science within the context of a specific biomedical discipline. The GPCI is supported by the UW Institute for Clinical and Translational Research https://ictr.wisc.edu/.

  • Quantification of very late xerostomia in head and neck cancer patients after irradiation Laryngoscope investigative otolaryngology
    Blitzer GC, Rogus-Pulia NM, Paz C, Nickel KP, Cannaday VL, Kelm-Nelson CA, Sudakaran S, Chappell RJ, Glazer T, Kimple RJ
    2022 Jul 12;7(4):1018-1024. doi: 10.1002/lio2.864. eCollection 2022 Aug.
    • More

      OBJECTIVE: Radiation therapy (RT) for head and neck cancer (HNC) can result in severe xerostomia, or the subjective feeling of dry mouth. Characterizing xerostomia is critical to designing future clinical trials investigating how to improve HNC patients' quality of life (QoL). Few studies have investigated the very late (>5 years post-RT) effects of RT for HNC. We undertook preliminary studies quantifying very late xerostomia.

      METHODS: Six adults who underwent RT for HNC at least 5 years prior and reported xerostomia were enrolled. Five healthy adults without a self-reported history of HNC or xerostomia were enrolled as controls. All participants completed three validated surveys to measure xerostomia-related QoL. Salivary production rates were measured and compositional analysis of the saliva and oral microbiome was completed.

      RESULTS: The QoL survey scores for the HNC participants were significantly worse as compared to the control participants. The HNC participants produced less unstimulated saliva (p = .02) but not less stimulated saliva. The median salivary mucin significantly higher in HNC participants than in control participants (p = .02). There was no significant difference between the pH, amylase, or total protein. Microbiome analysis revealed alpha diversity to be significantly lower in the HNC participants.

      CONCLUSION: In the survivors of HNC who suffer from late toxicities, multiple means of measuring toxicity may be useful. We found that in patients with radiation-induced xerostomia over 5 years after therapy, not only were the QoL surveys significantly worse, as expected, but other measurements such as mucin and oral microbiome diversity were also significantly different.

      LEVEL OF EVIDENCE: 3.

      PMID:36000048 | PMC:PMC9392383 | DOI:10.1002/lio2.864


      View details for PubMedID 36000048
  • Bimodal liquid biopsy for cancer immunotherapy based on peptide engineering and nanoscale analysis Biosensors & bioelectronics
    Bu J, Jeong W, Jafari R, Kubiatowicz LJ, Nair A, Poellmann MJ, Hong RS, Liu EW, Owen RH, Rawding PA, Hopkins CM, Kim D, George DJ, Armstrong AJ, Král P, Wang AZ, Bruce J, Zhang T, Kimple RJ, Hong S
    2022 Oct 1;213:114445. doi: 10.1016/j.bios.2022.114445. Epub 2022 Jun 1.
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      Despite its high potential, PD-L1 expressed by tumors has not been successfully utilized as a biomarker for estimating treatment responses to immunotherapy. Circulating tumor cells (CTCs) and tumor-derived exosomes that express PD-L1 can potentially be used as biomarkers; however, currently available assays lack clinically significant sensitivity and specificity. Here, a novel peptide-based capture surface is developed to effectively isolate PD-L1-expressing CTCs and exosomes from human blood. For the effective targeting of PD-L1, this study integrates peptide engineering strategies to enhance the binding strength and specificity of a β-hairpin peptide derived from PD-1 (pPD-1). Specifically, this study examines the effect of poly(ethylene glycol) spacers, the secondary peptide structure, and modification of peptide sequences (e.g., removal of biologically redundant amino acid residues) on capture efficiency. The optimized pPD-1 configuration captures PD-L1-expressing tumor cells and tumor-derived exosomes with 1.5-fold (p = 0.016) and 1.2-fold (p = 0.037) higher efficiencies, respectively, than their whole antibody counterpart (aPD-L1). This enhanced efficiency is translated into more clinically significant detection of CTCs (1.9-fold increase; p = 0.035) and exosomes (1.5-fold increase; p = 0.047) from patients' baseline samples, demonstrating stronger correlation with patients' treatment responses. Additionally, we confirmed that the clinical accuracy of our system can be further improved by co-analyzing the two biomarkers (bimodal CTC/exosome analysis). These data demonstrate that pPD-1-based capture is a promising approach for capturing PD-L1-expressing CTCs and exosomes, which can be used as a reliable biomarker for cancer immunotherapy.

      PMID:35679646 | DOI:10.1016/j.bios.2022.114445


      View details for PubMedID 35679646
  • Stress Keratin 17 Expression in Head and Neck Cancer Contributes to Immune Evasion and Resistance to Immune-Checkpoint Blockade Clinical cancer research : an official journal of the American Association for Cancer Research
    Wang W, Lozar T, Golfinos AE, Lee D, Gronski E, Ward-Shaw E, Hayes M, Bruce JY, Kimple RJ, Hu R, Harari PM, Xu J, Keske A, Sondel PM, Fitzpatrick MB, Dinh HQ, Lambert PF
    2022 Jul 1;28(13):2953-2968. doi: 10.1158/1078-0432.CCR-21-3039.
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      PURPOSE: We investigated whether in human head and neck squamous cell carcinoma (HNSCC) high levels of expression of stress keratin 17 (K17) are associated with poor survival and resistance to immunotherapy.

      EXPERIMENTAL DESIGN: We investigated the role of K17 in regulating both the tumor microenvironment and immune responsiveness of HNSCC using a syngeneic mouse HNSCC model, MOC2. MOC2 gives rise to immunologically cold tumors that are resistant to immune-checkpoint blockade (ICB). We engineered multiple, independent K17 knockout (KO) MOC2 cell lines and monitored their growth and response to ICB. We also measured K17 expression in human HNSCC of patients undergoing ICB.

      RESULTS: MOC2 tumors were found to express K17 at high levels. When knocked out for K17 (K17KO MOC2), these cells formed tumors that grew slowly or spontaneously regressed and had a high CD8+ T-cell infiltrate in immunocompetent syngeneic C57BL/6 mice compared with parental MOC2 tumors. This phenotype was reversed when we depleted mice for T cells. Whereas parental MOC2 tumors were resistant to ICB treatment, K17KO MOC2 tumors that did not spontaneously regress were eliminated upon ICB treatment. In a cohort of patients with HNSCC receiving pembrolizumab, high K17 expression correlated with poor response. Single-cell RNA-sequencing analysis revealed broad differences in the immune landscape of K17KO MOC2 tumors compared with parental MOC2 tumors, including differences in multiple lymphoid and myeloid cell types.

      CONCLUSIONS: We demonstrate that K17 expression in HNSCC contributes to immune evasion and resistance to ICB treatment by broadly altering immune landscapes of tumors.

      PMID:35621713 | PMC:PMC9250640 | DOI:10.1158/1078-0432.CCR-21-3039


      View details for PubMedID 35621713
  • Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer Neoplasia (New York, N.Y.)
    Carper MB, Goel S, Zhang AM, Damrauer JS, Cohen S, Zimmerman MP, Gentile GM, Parag-Sharma K, Murphy RM, Sato K, Nickel KP, Kimple RJ, Yarbrough WG, Amelio AL
    2022 Jul;29:100799. doi: 10.1016/j.neo.2022.100799. Epub 2022 Apr 30.
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      Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. Patients often present with locally advanced disease and a staggering 50% chance of relapse following treatment. Aberrant activation of adaptive response signaling pathways, such as the cAMP/PKA pathway, induce an array of genes associated with known cancer pathways that promote tumorigenesis and drug resistance. We identified the cAMP Regulated Transcription Coactivator 2 (CRTC2) to be overexpressed and constitutively activated in HNSCCs and this confers poor prognosis. CRTCs are regulated through their subcellular localization and we show that CRTC2 is exclusively nuclear in HPV(+) HNSCC, thus constitutively active, due to non-canonical Mitogen-Activated Kinase Kinase 1 (MEKK1)-mediated activation via a MEKK1-p38 signaling axis. Loss-of-function and pharmacologic inhibition experiments decreased CRTC2/CREB transcriptional activity by reducing nuclear CRTC2 via nuclear import inhibition and/or by eviction of CRTC2 from the nucleus. This shift in localization was associated with decreased proliferation, migration, and invasion. Our results suggest that small molecules that inhibit nuclear CRTC2 and p38 activity may provide therapeutic benefit to patients with HPV(+) HNSCC.

      PMID:35504112 | PMC:PMC9065880 | DOI:10.1016/j.neo.2022.100799


      View details for PubMedID 35504112
  • Using 4D dose accumulation to calculate organ-at-risk dose deviations from motion-synchronized liver and lung tomotherapy treatments Journal of applied clinical medical physics
    Ferris WS, Chao EH, Smilowitz JB, Kimple RJ, Bayouth JE, Culberson WS
    2022 Jul;23(7):e13627. doi: 10.1002/acm2.13627. Epub 2022 Apr 29.
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      Tracking systems such as Radixact Synchrony change the planned delivery of radiation during treatment to follow the target. This is typically achieved without considering the location changes of organs at risk (OARs). The goal of this work was to develop a novel 4D dose accumulation framework to quantify OAR dose deviations due to the motion and tracked treatment. The framework obtains deformation information and the target motion pattern from a four-dimensional computed tomography dataset. The helical tomotherapy treatment plan is split into 10 plans and motion correction is applied separately to the jaw pattern and multi-leaf collimator (MLC) sinogram for each phase based on the location of the target in each phase. Deformable image registration (DIR) is calculated from each phase to the references phase using a commercial algorithm, and doses are accumulated according to the DIR. The effect of motion synchronization on OAR dose was analyzed for five lung and five liver subjects by comparing planned versus synchrony-accumulated dose. The motion was compensated by an average of 1.6 cm of jaw sway and by an average of 5.7% of leaf openings modified, indicating that most of the motion compensation was from jaw sway and not MLC changes. OAR dose deviations as large as 19 Gy were observed, and for all 10 cases, dose deviations greater than 7 Gy were observed. Target dose remained relatively constant (D95% within 3 Gy), confirming that motion-synchronization achieved the goal of maintaining target dose. Dose deviations provided by the framework can be leveraged during the treatment planning process by identifying cases where OAR doses may change significantly from their planned values with respect to the critical constraints. The framework is specific to synchronized helical tomotherapy treatments, but the OAR dose deviations apply to any real-time tracking technique that does not consider location changes of OARs.

      PMID:35486094 | PMC:PMC9278681 | DOI:10.1002/acm2.13627


      View details for PubMedID 35486094
  • Prospective Study of PET/MRI Tumor Response During Chemoradiotherapy for Patients With Low-risk and Intermediate-risk p16-positive Oropharynx Cancer American journal of clinical oncology
    Witek ME, Kimple RJ, Avey GD, Burr AR, Chandereng T, Yu M, Hu R, Wieland AM, Labby ZE, Bruce JY, Brower JV, Hartig GK, Harari PM
    2022 May 1;45(5):202-207. doi: 10.1097/COC.0000000000000910. Epub 2022 Apr 12.
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      OBJECTIVE: The objective of this study was to examine tumor response with positron emission tomography (PET)/magnetic resonance imaging (MRI) during chemoradiotherapy as a predictor of outcome in patients with p16-positive oropharynx cancer.

      MATERIALS AND METHODS: Patients with p16-positive oropharynx cancer were treated with chemoradiotherapy. Low-risk (LR) disease was defined as T1-T3 and N0-2b and ≤10 pack-years and intermediate-risk (IR) disease as T4 or N2c-3 or >10 pack-years. Patients underwent a PET/MRI scan pretreatment and at fraction 10. Change in value of imaging means were analyzed by analysis of variance. K-means clustering with Euclidean distance functions were used for patient clustering. Silhouette width was used to determine the optimal number of clusters. Linear regression was performed on all radiographic metrics using patient and disease characteristics.

      RESULTS: Twenty-four patients were enrolled with 7 LR and 11 IR patients available for analysis. Pretreatment imaging characteristics between LR and IR patients were similar. Patients with LR disease exhibited a larger reduction in maximum standardized uptake value (SUV) compared with IR patients (P<0.05). Cluster analysis defined 2 cohorts that exhibited a similar intratreatment response. Cluster 1 contained 7 of 7 LR patients and 8 of 11 IR patients. Cluster 2 contained 3 of 11 IR patients. Cluster 2 exhibited significant differences compared with cluster 1 in the change in primary tumor peak SUV and largest lymph node median SUV.

      CONCLUSIONS: We identified that IR p16-positive oropharynx cancers exhibit heterogeneity in their PET/MRI response to chemoradiotherapy. These data support further study of intratreatment imaging response as a potential mechanism to identify patients with IR oropharynx cancer suitable for treatment deintensification.

      PMID:35446279 | DOI:10.1097/COC.0000000000000910


      View details for PubMedID 35446279
  • Advances in Organ Preservation for Laryngeal Cancer Current treatment options in oncology
    Campbell G, Glazer TA, Kimple RJ, Bruce JY
    2022 Apr;23(4):594-608. doi: 10.1007/s11864-022-00945-5. Epub 2022 Mar 18.
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      At the University of Wisconsin, all treatment of head and neck cancer patients begins with discussion at our multi-disciplinary tumor board. Most patients with T4 disease, with existing laryngeal dysfunction, considered unlikely to complete definitive CRT or who have a high risk of persistent aspiration after non-operative management undergo total laryngectomy. A laryngeal sparing approach is attempted on most other patients. Radiotherapy is delivered over 6.5 weeks, preferably with concurrent weekly cisplatin. If the patient is hesitant of chemotherapy or has contraindications to cisplatin, concurrent cetuximab may be offered. Patients treated with RT alone are often treated to the same dose, but via an accelerated schedule by adding a 6th fraction per week. The 6th fraction is given by delivering two treatments at least 6 h apart on a weekday of the patient's choosing. We consider the following to be major risk factors for clinically significant weight loss during treatment: a 10% or greater loss of weight in the 6 months prior to starting treatment, delivery of concurrent cisplatin, and treatment of the bilateral neck with radiation. Patients who have 2-3 of these characteristics are often given gastrostomy tubes prophylactically. Patients are seen 2 weeks after completion of therapy, and then every 3 months after completion for 2 years. A CT neck and PET-CT are performed at the first 3-month visit. They are seen twice in year three, and then yearly until years 5-7. At each of these visits, we have a low threshold to present the patient at our multidisciplinary tumor board for consideration of salvage laryngectomy if there are signs of progression.

      PMID:35303749 | PMC:PMC9405127 | DOI:10.1007/s11864-022-00945-5


      View details for PubMedID 35303749
  • Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction Cytotherapy
    Blitzer GC, Rogus-Pulia NM, Mattison RJ, Varghese T, Ganz O, Chappell R, Galipeau J, McDowell KA, Meyers RO, Glazer TA, Kimple RJ
    2022 May;24(5):534-543. doi: 10.1016/j.jcyt.2021.11.003. Epub 2022 Feb 16.
    • More

      BACKGROUND: Xerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ultimate source for replenishment of salivary gland tissue. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow-derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia.

      METHODS: This single-center phase 1 dose-escalation with expansion cohort, non-placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients' bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits.

      DISCUSSION: Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative.

      TRIAL REGISTRATION: World Health Organization International Clinical Trials Registry Platform: NCT04489732.

      PMID:35183442 | PMC:PMC9038658 | DOI:10.1016/j.jcyt.2021.11.003


      View details for PubMedID 35183442
  • Autophagy awakens-the myriad roles of autophagy in head and neck cancer development and therapeutic response Molecular carcinogenesis
    Bradley ST, Lee Y, Gurel Z, Kimple RJ
    2022 Feb;61(2):243-253. doi: 10.1002/mc.23372. Epub 2021 Nov 15.
    • More

      Autophagy is an evolutionarily conserved cell survival mechanism that degrades damaged proteins and organelles to generate cellular energy during times of stress. Recycling of these cellular components occurs in a series of sequential steps with multiple regulatory points. Mechanistic dysfunction can lead to a variety of human diseases and cancers due to the complexity of autophagy and its ability to regulate vital cellular functions. The role that autophagy plays in both the development and treatment of cancer is highly complex, especially given the fact that most cancer therapies modulate autophagy. This review aims to discuss the balance of autophagy in the development, progression, and treatment of head and neck cancer, as well as highlighting the need for a deeper understanding of what is still unknown about autophagy.

      PMID:34780672 | PMC:PMC8799495 | DOI:10.1002/mc.23372


      View details for PubMedID 34780672
  • Defining high-risk elective contralateral neck radiation volumes for oropharynx cancer Head & neck
    Witek ME, Woody NM, Musunuru HB, Hill PM, Yadav P, Burr AR, Ko HC, Ross RB, Kimple RJ, Harari PM
    2022 Feb;44(2):317-324. doi: 10.1002/hed.26924. Epub 2021 Nov 11.
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      BACKGROUND: To define the location of the initial contralateral lymph node (LN) metastasis in patients with oropharynx cancer.

      METHODS: The location of the LN centroids from patients with oropharynx cancer and a single radiographically positive contralateral LN was defined. A clinical target volume (CTV) inclusive of all LN centroids was created, and its impact on dose to organs at risk was assessed.

      RESULTS: We identified 55 patients of which 49/55 had a single contralateral LN in level IIA, 4/55 in level III, 1/55 in level IIB, and 1/55 in the retropharynx. Mean radiation dose to the contralateral parotid gland was 15.1 and 21.0 Gy, (p <0.001) using the modeled high-risk elective CTV and a consensus CTV, respectively.

      CONCLUSIONS: We present a systematic approach for identifying the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharynx cancer that warrants prospective clinical study.

      PMID:34761832 | DOI:10.1002/hed.26924


      View details for PubMedID 34761832
  • Retraction Science signaling
    Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, Stein AP, Salgia R, Rolff J, Kimple RJ, Wheeler DL
    2021 Nov 9;14(708):eabn0168. doi: 10.1126/scisignal.abn0168. Epub 2021 Nov 9.
  • Refining Elective Contralateral Neck Radiation Volumes for Oropharynx Cancer International journal of radiation oncology, biology, physics
    Witek M, Woody NM, Musunuru HB, Hill PM, Yadav P, Burr A, Ko HC, Kimple RJ, Harari PM
    2021 Nov 1;111(3S):e406. doi: 10.1016/j.ijrobp.2021.07.1171.
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      PURPOSE/OBJECTIVE(S): Judicious reduction in elective nodal volumes for patients with oropharyngeal squamous cell carcinoma (OPSCC) has the potential to reduce acute and long term toxicity while maintaining high rates of regional control. We postulated that the contralateral N0 neck region at highest risk for containing occult microscopic lymph node (LN) metastases in patients with OPSCC could be best defined by the location of the initial positive ipsilateral LN. We sought to identify and target this N0 elective neck region and assess impact on dose to organs at risk compared to using a consensus-defined contralateral elective nodal volume.

      MATERIALS/METHODS: We performed a retrospective review to identify patients with OPSCC and N2c disease as defined by a single radiographically positive LN. LN centroids were used to define the anatomic boundaries of the novel contralateral elective clinical target volume (ceCTV). Factors associated with LN centroid locations were assessed by the Fisher exact test. We used an external testing cohort to evaluate the robustness of ceCTV. The dosimetric impact of ceCTV compared to consensus elective nodal clinical target volumes (conCTV) was assessed with the t-test.

      RESULTS: We identified 25 patients that fit the selection criteria of which 84% had a single contralateral LN in level II and 16% in level III. We did not identify factors associated with LN centroid location. In the external data set, 97% (33/34) of the LN centroids were located within the novel elective contralateral target volume. Mean radiation dose to the contralateral parotid gland was 15.1 Gy (range 13.0-17.0 Gy) versus 21.0 Gy (range 18.0-24.0 Gy), P < 0.001 using the novel versus consensus elective contralateral nodal clinical target volumes, respectively.

      CONCLUSION: We present a systematic approach for considering the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharyngeal squamous cell carcinoma. These data support clinical study to evaluate this novel contralateral elective clinical target volume in patients with oropharyngeal squamous cell carcinoma who warrant elective contralateral neck radiotherapy.

      PMID:34701378 | DOI:10.1016/j.ijrobp.2021.07.1171


      View details for PubMedID 34701378
  • Mitophagy Induction by ROS-PINK1 Signaling Protects Head and Neck Cancer From Radiotherapy International journal of radiation oncology, biology, physics
    Lee YS, Bradley ST, Gurel Z, Nickel KP, Kimple RJ
    2021 Nov 1;111(3S):S56. doi: 10.1016/j.ijrobp.2021.07.145.
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      PURPOSE/OBJECTIVE(S): Approximate 25% of patients with local advanced head and neck cell carcinoma (HNSCC) treated with radiation still suffer from local relapse and are considered radiation resistant. We previously determined that radiation induces autophagy, a pro-survival cellular stress response, in HNSCC. In this study, we examine the consequence of autophagy inhibition and investigate the molecular mechanism underlying RT-induced autophagy.

      MATERIALS/METHODS: Autophagy was assessed using a nano-Luc LC3 reporter assay (Promega), immunoblotting and immunofluorescence for LC3 and acridine orange in multiple HNSCC cell lines. RNAi knockdown of EGFR, LAPTM4B and PINK1 were used to test the involved signaling molecules. CM-H2DCFDA was used as a measure of reactive oxygen species (ROS). Hydrogen peroxide was used to stimulate ROS production. Trolox, a ROS scavenger, was used to determine the correlation between ROS and RT-induced autophagy. Mitophagy determination was completed by using MitoTracker Red (Invitrogen) combined with immunofluorescence staining for LC3 and immunoblotting. Radiation was delivered using a RS225 cabinet irradiator at a dose rate of approximately 3 Gy/min with dose validation by TLD using custom, geometry specific phantoms. SAR405, a VPS34 inhibitor, was used to inhibit autophagy. A flank xenograft model using A253 cells was used to test the combination of autophagy inhibitors and radiotherapy in vivo.

      RESULTS: RT caused a two-fold increase in autophagy as assessed using the reporter assay and immunoblotting. Knockdown of EGFR and LAPTM4B, two proteins important in growth-factor deprivation induced autophagy, did not influence autophagy in RT-treated cells. RT did increase the accumulation of ROS (∼50%) and the dephosphorylation of mTOR (∼25%). Addition of Trolox to RT contributed to a considerable decrease in both ROS (∼50%) and autophagy (∼50%). RT also resulted in a mRNA elevation of PINK1 (∼1.6 fold), a mitochondrial modulator. Immunoblotting for LC3 in both the cytoplasmic and mitochondrial fraction indicated RT mostly increases mitophagy rather than bulk autophagy, which was confirmed using immunofluorescent staining for LC3 and MitoTracker red. Using a clonogenic survival assay, the combination of SAR405 and RT resulted in complete loss of cell survival suggesting a radiosensitizing effect. In vivo, SAR405 treatment combined with RT improved tumor control when compared to RT or SAR405 alone.

      CONCLUSION: RT-induced mitophagy involves ROS-PINK1 pathway and the regulation of mTOR. Inhibition of autophagy resulted in decreased cell survival in vitro and decreased in vivo tumor growth. These results suggest that targeting mitophagy may be a viable approach to sensitize HNSCC to radiation treatment.

      PMID:34700583 | DOI:10.1016/j.ijrobp.2021.07.145


      View details for PubMedID 34700583
  • Opioid use in patients undergoing treatment for oral cavity cancer Journal of pain management
    Ko HC, Mehra MN, Burr AR, Wieland AM, Kimple RJ, Hartig GK, Harari PM, Witek ME
    2020;13(2):167-173.
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      OBJECTIVE: In the context of the opioid epidemic, there is value in examining the use of opioids in specific cancer patient cohorts. We analyzed opioid use in patients undergoing adjuvant therapy for oral cavity cancer to define the incidence of new persistent use beyond 3 months.

      STUDY DESIGN: Retrospective.

      SETTING: Comprehensive academic cancer center.

      SUBJECTS AND METHODS: We performed a retrospective IRB-approved analysis of opioid use in patients who received adjuvant radiotherapy with or with concurrent systemic therapy for surgically resected oral cavity cancer between 2003 and 2016. Factors associated with opioid use were evaluated by Chi-square test and one-way ANOVA. The Kaplan-Meier method was used to estimate overall survival.

      RESULTS: Of 77 identified patients, 10 (13%) patients received opioid prescriptions at 3 months or greater following completion of radiotherapy. Patients who were opioid naive prior to surgery required significantly fewer opioid prescriptions than intermittent or chronic opioid users. No specific factors were associated with new persistent opioid use.

      CONCLUSIONS: Patients undergoing surgery and adjuvant radiotherapy for oral cavity cancer who required opioids for cancer treatment related pain are at minimal risk for new dependency. Judicious pain management should be applied for patients with a history of prior opioid use. Larger patient cohorts will be needed to identify patient, disease, and treatment characteristics associated with new persistent use given its limited incidence.

      PMID:34457108 | PMC:PMC8388255


      View details for PubMedID 34457108
  • Biology of HPV Mediated Carcinogenesis and Tumor Progression Seminars in radiation oncology
    Cosper PF, Bradley S, Luo L, Kimple RJ
    2021 Oct;31(4):265-273. doi: 10.1016/j.semradonc.2021.02.006.
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      Human papillomavirus (HPV) is a ubiquitous DNA virus that infects squamous epithelia. Though HPV only encodes 8 genes, it is capable of causing cellular transformation and ultimately cancer in host cells. In this article we review the classification of HPV viruses, their genetic structure and life cycle, viral gene biology, and provide an overview of the role of HPV in cancer. We explain how the viral life cycle can lead to integration of viral DNA into the host genome leading to increased cell cycle progression, decreased apoptosis, altered DNA repair, and chromosomal instability. We describe the multifaceted roles of the canonical oncogenes E6 and E7 in promoting tumorigenesis and the important role of other viral genes in regulating cancer development. We also review how the virus actively suppresses innate and adaptive immunity to evade immune detection and promote a pro-tumorigenic microenvironment. The biology presented here will serve as a foundation to the other chapters in this edition and we hope it will incite enthusiasm for continued research on this fascinating virus that causes significant morbidity and mortality worldwide.

      PMID:34455982 | PMC:PMC8409095 | DOI:10.1016/j.semradonc.2021.02.006


      View details for PubMedID 34455982
  • ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts Molecular cancer therapeutics
    Baschnagel AM, Elnaggar JH, VanBeek HJ, Kromke AC, Skiba JH, Kaushik S, Abel L, Clark PA, Longhurst CA, Nickel KP, Leal TA, Zhao SG, Kimple RJ
    2021 Nov;20(11):2129-2139. doi: 10.1158/1535-7163.MCT-21-0305. Epub 2021 Aug 19.
    • More

      M6620, a selective ATP-competitive inhibitor of the ATM and RAD3-related (ATR) kinase, is currently under investigation with radiation in patients with non-small cell lung cancer (NSCLC) brain metastases. We evaluated the DNA damage response (DDR) pathway profile of NSCLC and assessed the radiosensitizing effects of M6620 in a preclinical NSCLC brain metastasis model. Mutation analysis and transcriptome profiling of DDR genes and pathways was performed on NSCLC patient samples. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, cell cycle, and DNA damage signaling and repair assays. NSCLC brain metastasis patient-derived xenograft models were used to assess intracranial response and overall survival. In vivo IHC was performed to confirm in vitro results. A significant portion of NSCLC patient tumors demonstrated enrichment of DDR pathways. DDR pathways correlated with lung squamous cell histology; and mutations in ATR, ATM, BRCA1, BRCA2, CHEK1, and CHEK2 correlated with enrichment of DDR pathways in lung adenocarcinomas. M6620 reduced colony formation after radiotherapy and resulted in inhibition of DNA DSB repair, abrogation of the radiation-induced G2 cell checkpoint, and formation of dysfunctional micronuclei, leading to enhanced radiation-induced mitotic death. The combination of M6620 and radiation resulted in improved overall survival in mice compared with radiation alone. In vivo IHC revealed inhibition of pChk1 in the radiation plus M6620 group. M6620 enhances the effect of radiation in our preclinical NSCLC brain metastasis models, supporting the ongoing clinical trial (NCT02589522) evaluating M6620 in combination with whole brain irradiation in patients with NSCLC brain metastases.

      PMID:34413128 | PMC:PMC8571002 | DOI:10.1158/1535-7163.MCT-21-0305


      View details for PubMedID 34413128
  • Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft <em>Versus</em> Host Disease Frontiers in immunology
    Chinnadurai R, Bates PD, Kunugi KA, Nickel KP, DeWerd LA, Capitini CM, Galipeau J, Kimple RJ
    2021 Jul 26;12:708950. doi: 10.3389/fimmu.2021.708950. eCollection 2021.
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      Mesenchymal stromal cells (MSCs) are being tested as a cell therapy in clinical trials for dozens of inflammatory disorders, with varying levels of efficacy reported. Suitable and robust preclinical animal models for testing the safety and efficacy of different types of MSC products before use in clinical trials are rare. We here introduce two highly robust animal models of immune pathology: 1) acute radiation syndrome (ARS) and 2) graft versus host disease (GvHD), in conjunction with studying the immunomodulatory effect of well-characterized Interferon gamma (IFNγ) primed bone marrow derived MSCs. The animal model of ARS is based on clinical grade dosimetry precision and bioluminescence imaging. We found that allogeneic MSCs exhibit lower persistence in naïve compared to irradiated animals, and that intraperitoneal infusion of IFNγ prelicensed allogeneic MSCs protected animals from radiation induced lethality by day 30. In direct comparison, we also investigated the effect of IFNγ prelicensed allogeneic MSCs in modulating acute GvHD in an animal model of MHC major mismatched bone marrow transplantation. Infusion of IFNγ prelicensed allogeneic MSCs failed to mitigate acute GvHD. Altogether our results demonstrate that infused IFNγ prelicensed allogeneic MSCs protect against lethality from ARS, but not GvHD, thus providing important insights on the dichotomy of IFNγ prelicensed allogenic MSCs in well characterized and robust animal models of acute tissue injury.

      PMID:34386012 | PMC:PMC8352793 | DOI:10.3389/fimmu.2021.708950


      View details for PubMedID 34386012
  • RTAnswers Online Patient Education Materials Deviate From Recommended Reading Levels Applied radiation oncology
    Rosenberg SA, Denu RA, Francis D, Hullett CR, Fisher M, Schuster JM, Bassetti MF, Kimple RJ
    2018;7(2):26-30. Epub 2018 Jun 19.
    • More

      OBJECTIVE: Patients are turning to the Internet more often for cancer-related information. Oncology organizations need to ensure that appropriately written information is available for patients online. The aim of this study was to determine whether the readability of radiation oncology online patient information (OPI) provided by RTAnswers (RTAnswers.org, created by the American Society for Radiation Oncology) is written at a sixth-grade level as recommended by the National Institutes of Health (NIH), the U.S Department of Health and Human Services (HHS), and the American Medical Association (AMA).

      METHODS: RTanswers.org was accessed and online patient-oriented brochures for 13 specific disease sites were analyzed. Readability of OPI from RTAnswers was assessed using 10 common readability tests: New Dale-Chall Test, Flesch Reading Ease Score, Coleman-Liau Index, Flesch-Kinkaid Grade Level, FORCAST test, Fry Score, Simple Measure of Gobbledygook, Gunning Frequency of Gobbledygook, New Fog Count, and Raygor Readability Estimate.

      RESULTS: A composite grade level of readability was constructed using the 8 readability measures that provide a single grade-level output. The grade levels computed by each of these 8 tests were highly correlated (SI alpha = 0.98). The composite grade level for these disease site-specific brochures was 11.6 ± 0.83, corresponding to a senior in high school, significantly higher than the target sixth-grade level (p < 0.05) recommended by the NIH, HHS, and AMA.

      CONCLUSION: Patient educational material provided by RTAnswers.org is written significantly above the target reading level. Simplifying and rewording this information could improve patients' understanding of radiation therapy and improve treatment adherence and outcomes.

      PMID:34169120 | PMC:PMC8221236


      View details for PubMedID 34169120
  • Impact of immediate cryopreservation on the establishment of patient derived xenografts from head and neck cancer patients Journal of translational medicine
    Abel L, Durmaz A, Hu R, Longhurst C, Baschnagel AM, Wheeler D, Scott JG, Kimple RJ
    2021 Apr 28;19(1):180. doi: 10.1186/s12967-021-02850-1.
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      BACKGROUND: Patient-derived xenografts established from human cancers are important tools for investigating novel anti-cancer therapies. Establishing PDXs requires a significant investment and many PDXs may be used infrequently due to their similarity to existing models, their growth rate, or the lack of relevant mutations. We performed this study to determine whether we could efficiently establish PDXs after cryopreservation to allow molecular profiling to be completed prior to implanting the human cancer.

      METHODS: Fresh tumor was split with half used to establish a PDX immediately and half cryopreserved for later implantation. Resulting tumors were assessed histologically and tumors established from fresh or cryopreserved tissues compared as to the growth rate, extent of tumor necrosis, mitotic activity, keratinization, and grade. All PDXs were subjected to short tandem repeat testing to confirm identity and assess similarity between methods.

      RESULTS: Tumor growth was seen in 70% of implanted cases. No growth in either condition was seen in 30% of tumors. One developed a SCC from the immediate implant but a lymphoproliferative mass without SCC from the cryopreserved specimen. No difference in growth rate was seen. No difference between histologic parameters was seen between the two approaches.

      CONCLUSIONS: Fresh human cancer tissue can be immediately cryopreserved and later thawed and implanted to establish PDXs. This resource saving approach allows for tumor profiling prior to implantation into animals thus maximizing the probability that the tumor will be utilized for future research.

      PMID:33910584 | PMC:PMC8082827 | DOI:10.1186/s12967-021-02850-1


      View details for PubMedID 33910584
  • Clinical Cancer Advances 2021: ASCO's Report on Progress Against Cancer Journal of clinical oncology : official journal of the American Society of Clinical Oncology
    Smith SM, Wachter K, Burris HA, Schilsky RL, George DJ, Peterson DE, Johnson ML, Markham MJ, Mileham KF, Beg MS, Bendell JC, Dreicer R, Keedy VL, Kimple RJ, Knoll MA, LoConte N, MacKay H, Meisel JL, Moynihan TJ, Mulrooney DA, Mulvey TM, Odenike O, Pennell NA, Reeder-Hayes K, Smith C, Sullivan RJ, Uzzo R
    2021 Apr 1;39(10):1165-1184. doi: 10.1200/JCO.20.03420. Epub 2021 Feb 2.
  • Immunotherapy in Head and Neck Cancer-Ready for Prime Time or More Research Needed? International journal of radiation oncology, biology, physics
    Karam SD, Anderson CM, Ma D, Chua LK, Kimple RJ
    2021 Mar 1;109(3):647-650. doi: 10.1016/j.ijrobp.2020.11.022.
    • More

      PMID:33516431 | PMC:PMC8597385 | DOI:10.1016/j.ijrobp.2020.11.022


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  • Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases Scientific reports
    Baschnagel AM, Kaushik S, Durmaz A, Goldstein S, Ong IM, Abel L, Clark PA, Gurel Z, Leal T, Buehler D, Iyer G, Scott JG, Kimple RJ
    2021 Jan 28;11(1):2520. doi: 10.1038/s41598-021-81832-1.
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      Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

      PMID:33510214 | PMC:PMC7843608 | DOI:10.1038/s41598-021-81832-1


      View details for PubMedID 33510214
  • Mentorship Initiatives in Radiation Oncology: A Scoping Review of the Literature International journal of radiation oncology, biology, physics
    Marsiglio JA, Rosenberg DM, Rooney MK, Goodman CR, Gillespie EF, Hirsch AE, Holliday EB, Kimple RJ, Thomas CR, Golden DW
    2021 Jun 1;110(2):292-302. doi: 10.1016/j.ijrobp.2020.12.049. Epub 2021 Jan 4.
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      PURPOSE: Although mentorship is described extensively in academic medical literature, there are few descriptions of mentorship specific to radiation oncology. The goal of the current study was to investigate the state of mentorship in radiation oncology through a scoping review of the literature.

      METHODS AND MATERIALS: A search protocol was defined according to Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for scoping reviews (PRISMA-ScR) guidelines. Predefined search terms and medical subject headings were used to search PubMed for English language articles published after January 1, 1990, on mentorship in radiation oncology. Additionally, in-press articles from major radiation oncology and medical education journals were searched. Three reviewers determined article eligibility. Included articles were classified based on predefined evaluation criteria.

      RESULTS: Fourteen publications from 2008 to 2019 met inclusion criteria. The most commonly described form of mentorship was the dyad (64.3%), followed by team (14.3%) and peer (7.1%); 2 articles did not specify mentorship type (14.3%). The most commonly mentored participants were residents (35.7%), followed by medical students (35.7%) and attendings (21.4%); 1 study included participants of all levels (7.1%). Thirteen studies (92.9%) identified an experimental study design, most of which were cross-sectional (42.9%), followed by cohort studies (28.6%) and before/after (21.4%). Median sample size, reported in 12 of 13 experimental studies, was 132 (coefficient of variation, 1.06). Although outcomes varied widely, the majority described successful implementation of mentorship initiatives with high levels of participant satisfaction.

      CONCLUSIONS: Although few initiatives are currently reported, the present study suggests that these initiatives are successful in promoting career development and increasing professional satisfaction. The interventions overwhelmingly described mentorship dyads; other forms of mentorship are either less common or understudied. Limitations included interventions not being evaluated in a controlled setting, and many were assessed using surveys with low response rates. This review highlights rich opportunities for future scholarship to develop, evaluate, and disseminate radiation oncology mentorship initiatives.

      PMID:33412265 | PMC:PMC8122025 | DOI:10.1016/j.ijrobp.2020.12.049


      View details for PubMedID 33412265
  • AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer Clinical cancer research : an official journal of the American Association for Cancer Research
    McDaniel NK, Iida M, Nickel KP, Longhurst CA, Fischbach SR, Rodems TS, Kranjac CA, Bo AY, Luo Q, Gallagher MM, Welke NB, Mitchell KR, Schulz AE, Eckers JC, Hu R, Salgia R, Hong S, Bruce JY, Kimple RJ, Wheeler DL
    2020 Aug 15;26(16):4349-4359. doi: 10.1158/1078-0432.CCR-19-3142. Epub 2020 May 21.
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      PURPOSE: Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment.

      EXPERIMENTAL DESIGN: To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines.

      RESULTS: Treatment of cetuximab- and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models.

      CONCLUSIONS: Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.

      PMID:32439698 | PMC:PMC7442604 | DOI:10.1158/1078-0432.CCR-19-3142


      View details for PubMedID 32439698
  • Follow-Up and Management of Patients With Head and Neck Cancer During the 2019 Novel Coronavirus (SARS-CoV-2) Disease Pandemic Advances in radiation oncology
    Chua LK, Ma DJ, Anderson CM, Karam SD, Margalit DN, Kimple RJ
    2020 May 15;5(4):631-636. doi: 10.1016/j.adro.2020.04.031. eCollection 2020 Jul-Aug.
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      PMID:32426556 | PMC:PMC7227497 | DOI:10.1016/j.adro.2020.04.031


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  • Immunoavidity-Based Capture of Tumor Exosomes Using Poly(amidoamine) Dendrimer Surfaces Nano letters
    Poellmann MJ, Nair A, Bu J, Kim KH, Kimple RJ, Hong S
    2020 Aug 12;20(8):5686-5692. doi: 10.1021/acs.nanolett.0c00950. Epub 2020 May 19.
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      Tumor-derived blood-circulating exosomes have potential as a biomarker to greatly improve cancer treatment. However, effective isolation of exosomes remains a tremendous technical challenge. This study presents a novel nanostructured polymer surface for highly effective capture of exosomes through strong avidity. Various surface configurations, consisting of multivalent dendrimers, PEG, and tumor-targeting antibodies, were tested using exosomes isolated from tumor cell lines. We found that a dual layer dendrimer configuration exhibited the highest efficiency in capturing cultured exosomes spiked into human serum. Importantly, the optimized surface captured a > 4-fold greater amount of tumor exosomes from head and neck cancer patient plasma samples than that from healthy donors. Nanomechanical analysis using atomic force microscopy also revealed that the enhancement was attributed to multivalent binding (avidity) and augmented short-range adhesion mediated by dendrimers. Our results support that the dendrimer surface detects tumor exosomes at high sensitivity and specificity, demonstrating its potential as a new cancer liquid biopsy platform.

      PMID:32407121 | DOI:10.1021/acs.nanolett.0c00950


      View details for PubMedID 32407121
  • FGFR Inhibition Enhances Sensitivity to Radiation in Non-Small Cell Lung Cancer Molecular cancer therapeutics
    SenthilKumar G, Fisher MM, Skiba JH, Miller MC, Brennan SR, Kaushik S, Bradley ST, Longhurst CA, Buehler D, Nickel KP, Iyer G, Kimple RJ, Baschnagel AM
    2020 Jun;19(6):1255-1265. doi: 10.1158/1535-7163.MCT-19-0931. Epub 2020 May 5.
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      FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.

      PMID:32371583 | PMC:PMC7272291 | DOI:10.1158/1535-7163.MCT-19-0931


      View details for PubMedID 32371583
  • Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas International journal of radiation oncology, biology, physics
    Fisher MM, SenthilKumar G, Hu R, Goldstein S, Ong IM, Miller MC, Brennan SR, Kaushik S, Abel L, Nickel KP, Iyer G, Harari PM, Kimple RJ, Baschnagel AM
    2020 Jul 15;107(4):793-803. doi: 10.1016/j.ijrobp.2020.03.040. Epub 2020 Apr 13.
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      PURPOSE: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.

      METHODS AND MATERIALS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models.

      RESULTS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX.

      CONCLUSIONS: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

      PMID:32298810 | PMC:PMC7321889 | DOI:10.1016/j.ijrobp.2020.03.040


      View details for PubMedID 32298810
  • Four Influential Clinical Trials in Human Papilloma Virus-Associated Oropharynx Cancer International journal of radiation oncology, biology, physics
    Margalit DN, Karam SD, Chua LK, Anderson C, Kimple RJ
    2020 Apr 1;106(5):893-899. doi: 10.1016/j.ijrobp.2019.12.015.
  • Interstitial diffuse optical probe with spectral fitting to measure dynamic tumor hypoxia Biomedical physics & engineering express
    Fru LC, Jacques SL, Nickel KP, Varghese T, Kissick MW, DeWerd LA, Kimple RJ
    2020 Jan;6(1):10.1088/2057-1976/ab6e16. doi: 10.1088/2057-1976/ab6e16. Epub 2020 Jan 31.
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      Understanding the dynamic nature of tumor hypoxia is vital for cancer therapy. The presence of oxygen within a tumor during radiation therapy increases the likelihood of local control. We used a novel interstitial diffuse optical probe to make real-time measurements of blood volume fraction and hemoglobin oxygen saturation within a tumor at a high temporal resolution. This device was initially characterized and benchmarked using a customized vessel designed to control hemoglobin oxygen saturation and blood volume in a solution of blood with different concentrations of an oxygen scavenger, tetrakis (hydroxymethyl) phosphonium chloride. The optical device was found to consistently monitor the changes in oxygen saturation and these changes correlated to the concentration of the oxygen scavenger added. In near-simultaneous measurements of blood volume and oxygen saturation in tumor-bearing mice, the changes in blood volume fraction and oxygen saturation measured with the interstitial diffuse optical probe were benchmarked against photoacoustic imaging system to track and compare temporal dynamics of oxygen saturation and blood volume in a patient-derived xenograft model of hypopharyngeal carcinoma. Positive correlations between our device and photoacoustic imaging in measuring blood volume and oxygen saturation were observed.

      PMID:32095273 | PMC:PMC7039661 | DOI:10.1088/2057-1976/ab6e16


      View details for PubMedID 32095273
  • Patient Derived Models to Study Head and Neck Cancer Radiation Response Cancers
    Cosper PF, Abel L, Lee Y, Paz C, Kaushik S, Nickel KP, Alexandridis R, Scott JG, Bruce JY, Kimple RJ
    2020 Feb 12;12(2):419. doi: 10.3390/cancers12020419.
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      Patient-derived model systems are important tools for studying novel anti-cancer therapies. Patient-derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for the study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient-derived models for radiation research, including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

      PMID:32059418 | PMC:PMC7072508 | DOI:10.3390/cancers12020419


      View details for PubMedID 32059418
  • Clinical outcomes for larynx patients with cancer treated with refinement of high-dose radiation treatment volumes Head & neck
    Burr AR, Harari PM, Haasl AM, Wieland AM, Bruce JY, Kimple RJ, Hartig GK, McCulloch TM, Witek ME
    2020 Aug;42(8):1874-1881. doi: 10.1002/hed.26098. Epub 2020 Feb 14.
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      BACKGROUND: To evaluate disease control, toxicities, and dose to dysphagia/aspiration risk structures (DARS) using a direct gross tumor volume (GTV70Gy ) to planning target volume expansion (dPTV70Gy ) for patients with squamous cell carcinoma of the larynx (LSCC).

      METHODS: A retrospective review was performed on patients with LSCC treated between 2003 and 2018. Clinical outcomes, toxicities, and dosimetric data were analyzed.

      RESULTS: Seventy-three patients were identified. Overall survival at 5-years was 57.8%. Five-year local and regional control was 79.8% and 88.2%, respectively. Distant metastatic-only failure was 2.7%. Eighty percent of failures were 95% contained within the dPTV70Gy . Mean dose and the volume of DARS receiving 70 Gy was significantly lower for dPTV70Gy compared to a consensus-defined PTV70Gy .

      DISCUSSION: Judicious reduction in high-dose target volumes can preserve high tumor control rates while reducing dose to normal surrounding structures underscoring the potential benefit of this approach in enabling local therapy intensification to improve locoregional control.

      PMID:32057151 | PMC:PMC7369226 | DOI:10.1002/hed.26098


      View details for PubMedID 32057151
  • Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology Journal of clinical oncology : official journal of the American Society of Clinical Oncology
    Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, Chang SM, Dale W, Diefenbach SM, Rodriguez-Galindo C, George DJ, Gilligan TD, Harvey RD, Johnson ML, Kimple RJ, Knoll MA, LoConte N, Maki RG, Meisel JL, Meyerhardt JA, Pennell NA, Rocque GB, Sabel MS, Schilsky RL, Schneider BJ, Tap WD, Uzzo RG, Westin SN
    2020 Apr 1;38(10):1081. doi: 10.1200/JCO.19.03141. Epub 2020 Feb 4.
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      Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.

      PMID:32013670 | DOI:10.1200/JCO.19.03141


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  • STAT-ART: The Promise and Practice of a Rapid Palliative Single Session of MR-Guided Online Adaptive Radiotherapy (ART) Frontiers in oncology
    Mittauer KE, Hill PM, Geurts MW, Costa AD, Kimple RJ, Bassetti MF, Bayouth JE
    2019 Oct 22;9:1013. doi: 10.3389/fonc.2019.01013. eCollection 2019.
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      This work describes a novel application of MR-guided online adaptive radiotherapy (MRgoART) in the management of patients whom urgent palliative care is indicated using statum-adaptive radiotherapy (STAT-ART). The implementation of STAT-ART, as performed at our institution, is presented including a discussion of the advantages and limitations compared to the standard of care for palliative radiotherapy on conventional c-arm linacs. MR-based treatment planning techniques of STAT-ART for density overrides and deformable image registration (DIR) of diagnostic CT to the treatment MR are also addressed.

      PMID:31696053 | PMC:PMC6817496 | DOI:10.3389/fonc.2019.01013


      View details for PubMedID 31696053
  • Effects of culture method on response to EGFR therapy in head and neck squamous cell carcinoma cells Scientific reports
    Ayuso JM, Vitek R, Swick AD, Skala MC, Wisinski KB, Kimple RJ, Lambert PF, Beebe DJ
    2019 Aug 28;9(1):12480. doi: 10.1038/s41598-019-48764-3.
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      The EGFR pathway plays a critical role in head and neck squamous cell carcinoma (HNSCC). Targeted therapies against the EGFR are utilized as a treatment for HNSCCC. However, patient response is heterogeneous and molecular biomarkers are lacking to predict patient response. Therefore, functional assays where drug response is directly evaluated in tumor cells are an interesting alternative. Previous studies have shown that experimental conditions modify the drug response observed in functional assays. Thus, in this work the influence of the culture environment on response to Cetuximab (EGFR monoclonal antibody) and AZD8055 (mTOR inhibitor) was evaluated. HNSCC UM-SCC-1 and UM-SCC-47 cells were cultured in 2D monoculture and compared with: 2D co-culture with cancer-associated fibroblasts (CAF); 3D culture in collagen hydrogels; and 3D culture in tumor spheroids. The results showed UM-SCC-1 drug response significantly changed in the different culture environments; leading to an increase in drug resistance in the CAF co-culture and the 3D spheroids. Conversely, UM-SCC-47 exhibited a more constant drug response across culture conditions. In conclusion, this work highlights the importance of culture conditions that modulate response to EGFR pathway inhibition.

      PMID:31462653 | PMC:PMC6713778 | DOI:10.1038/s41598-019-48764-3


      View details for PubMedID 31462653
  • High-throughput quantitative detection of basal autophagy and autophagic flux using image cytometry BioTechniques
    SenthilKumar G, Skiba JH, Kimple RJ
    2019 Aug;67(2):70-73. doi: 10.2144/btn-2019-0044. Epub 2019 Jun 26.
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      Quantitative assessment of changes in macro-autophagy is often performed through manual quantification of the number of LC3B foci in immunofluorescence microscopy images. This method is highly laborious, subject to image-field selection and foci-counting bias, and is not sensitive for analyzing changes in basal autophagy. Alternative methods such as flow cytometry and transmission electron microscopy require highly specialized, expensive instruments and time-consuming sample preparation. Immunoblots are prone to exposure-related variations and noise that prevents accurate quantification. We report a high-throughput, inexpensive, reliable and objective method for studying basal level and flux changes in late-stage autophagy using image cytometry and acridine orange staining.

      PMID:31238709 | PMC:PMC7141596 | DOI:10.2144/btn-2019-0044


      View details for PubMedID 31238709
  • De-Escalation Strategies in HPV-Associated Oropharynx Cancer-Are we Putting the Cart Before the Horse? International journal of radiation oncology, biology, physics
    Anderson CM, Kimple RJ, Lin A, Karam SD, Margalit DN, Chua LK
    2019 Jul 15;104(4):705-709. doi: 10.1016/j.ijrobp.2019.02.054.
    • More

      PMID:31204653 | PMC:PMC7194352 | DOI:10.1016/j.ijrobp.2019.02.054


      View details for PubMedID 31204653
  • Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation Clinical cancer research : an official journal of the American Association for Cancer Research
    Pasch CA, Favreau PF, Yueh AE, Babiarz CP, Gillette AA, Sharick JT, Karim MR, Nickel KP, DeZeeuw AK, Sprackling CM, Emmerich PB, DeStefanis RA, Pitera RT, Payne SN, Korkos DP, Clipson L, Walsh CM, Miller D, Carchman EH, Burkard ME, Lemmon KK, Matkowskyj KA, Newton MA, Ong IM, Bassetti MF, Kimple RJ, Skala MC, Deming DA
    2019 Sep 1;25(17):5376-5387. doi: 10.1158/1078-0432.CCR-18-3590. Epub 2019 Jun 7.
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      PURPOSE: Cancer treatment is limited by inaccurate predictors of patient-specific therapeutic response. Therefore, some patients are exposed to unnecessary side effects and delays in starting effective therapy. A clinical tool that predicts treatment sensitivity for individual patients is needed.

      EXPERIMENTAL DESIGN: Patient-derived cancer organoids were derived across multiple histologies. The histologic characteristics, mutation profile, clonal structure, and response to chemotherapy and radiation were assessed using bright-field and optical metabolic imaging on spheroid and single-cell levels, respectively.

      RESULTS: We demonstrate that patient-derived cancer organoids represent the cancers from which they were derived, including key histologic and molecular features. These cultures were generated from numerous cancers, various biopsy sample types, and in different clinical settings. Next-generation sequencing reveals the presence of subclonal populations within the organoid cultures. These cultures allow for the detection of clonal heterogeneity with a greater sensitivity than bulk tumor sequencing. Optical metabolic imaging of these organoids provides cell-level quantification of treatment response and tumor heterogeneity allowing for resolution of therapeutic differences between patient samples. Using this technology, we prospectively predict treatment response for a patient with metastatic colorectal cancer.

      CONCLUSIONS: These studies add to the literature demonstrating feasibility to grow clinical patient-derived organotypic cultures for treatment effectiveness testing. Together, these culture methods and response assessment techniques hold great promise to predict treatment sensitivity for patients with cancer undergoing chemotherapy and/or radiation.

      PMID:31175091 | PMC:PMC6726566 | DOI:10.1158/1078-0432.CCR-18-3590


      View details for PubMedID 31175091
  • Reducing radiotherapy target volume expansion for patients with HPV-associated oropharyngeal cancer Oral oncology
    Burr AR, Harari PM, Ko HC, Bruce JY, Kimple RJ, Witek ME
    2019 May;92:52-56. doi: 10.1016/j.oraloncology.2019.03.013. Epub 2019 Mar 22.
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      PURPOSE: To evaluate clinical outcomes and patterns of failure using a direct gross tumor volume to planning target volume expansion in patients with p16-positive oropharyngeal squamous cell carcinoma.

      METHODS AND MATERIALS: We performed a retrospective review of patients with p16-positive oropharyngeal squamous cell carcinomas treated between 2002 and 2017 with primary radiotherapy with or without concurrent systemic therapy. Patient and disease characteristics associated with disease control and clinical outcomes were analyzed by Cox proportional hazards regression and Kaplan-Meier analyses. Imaging at the time of first failure was used to categorize failure patterns.

      RESULTS: We identified 134 patients with a median follow-up of 56.2 months (range 8.2-160.2 months). Local and regional control at 5 years was 91.5% (95% CI: 86.8-96.4%), and 90.8% (95% CI: 85.6-96.2%), respectively. Of the 14 locoregional failures, there were 10 in-field (Type A), 3 marginal (Type B), and 1 geographic (Type E). Age >70 years (HR 5.42; 95% CI: 1.87-15.68) and T4 versus T1-3 (HR 4.09; 95% CI: 1.01-2.65) were associated with increased rates of locoregional failure on multivariate analysis. The rate of gastrostomy tube retention at one year was 6.0% (range 2.8-12.7%).

      CONCLUSIONS: Management of patients with p16-positive oropharyngeal squamous cell carcinoma using definitive radiotherapy and a high-dose planning target volume created without a gross tumor volume to clinical tumor volume expansion resulted in high locoregional control with the vast majority of failures occurring within the high-dose field. These data warrant prospective evaluation of this technique as a therapy de-intensification approach.

      PMID:31010623 | PMC:PMC7062456 | DOI:10.1016/j.oraloncology.2019.03.013


      View details for PubMedID 31010623
  • The ASTRO Research Portfolio: Where Do We Go From Here? International journal of radiation oncology, biology, physics
    Yu JB, Beck TF, Anscher MS, Baschnagel AM, Brock KK, Carlson DJ, Dominello MM, Kimple RJ, Knisely PS, Mendonca MS, Mian OY, Singh AK, Moros EG, Keen JC
    2019 Feb 1;103(2):308-309. doi: 10.1016/j.ijrobp.2018.09.009.
  • Analysis of the 2017 American Society for Radiation Oncology (ASTRO) Research Portfolio International journal of radiation oncology, biology, physics
    Yu JB, Beck TF, Anscher MS, Baschnagel AM, Brock KK, Carlson DJ, Dominello MM, Kimple RJ, Knisely JP, Mendonca MS, Mian OY, Singh AK, Moros EG, Keen JC
    2019 Feb 1;103(2):297-304. doi: 10.1016/j.ijrobp.2018.07.2056.
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      PURPOSE: Research in radiation oncology (RO) is imperative to support the discovery of new uses of radiation and improvement of current approaches to radiation delivery and to foster the continued evolution of our field. Therefore, in 2016, the American Society of Radiation Oncology performed an evaluation of research grant funding for RO.

      METHODS AND MATERIALS: Members of the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) were asked about funded and unfunded grants that were submitted by their departments between the fiscal years 2014 and 2016. Grants were grouped according to broad categories defined by the 2017 American Society of Radiation Oncology Research Agenda. Additionally, active grants in the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools database were collated using RO faculty names.

      RESULTS: Overall, there were 816 funded (44%) and 1031 unfunded (56%) SCAROP-reported grants. Total grant funding was over $196 million. The US government funded the plurality (42.2%; 345 of 816) of grants compared with nonprofit and industry funders. Investigators from 10 institutions accounted for >75% of funded grants. Of the funded grants, 43.5% were categorized as "genomic influences and targeted therapies." The proportion of funded to unfunded grants was highest within the category of "tumor microenvironment, normal tissue effects, and reducing toxicity" (53.4% funded). "New clinical trial design and big data" had the smallest share of SCAROP grant applications and the lowest percent funded (38.3% of grants). NIH grants to RO researchers in 2014 to 2016 accounted for $85 million in funding. From the 31 responding SCAROP institutions, there was a 28% average success rate for RO proposals submitted to the NIH during this period.

      CONCLUSIONS: Though RO researchers from responding institutions were relatively successful in obtaining funding, the overall amount awarded remains small. Continued advocacy on behalf of RO is needed, as well as investment to make research careers more attractive areas for emerging faculty.

      PMID:30647006 | DOI:10.1016/j.ijrobp.2018.07.2056


      View details for PubMedID 30647006
  • Correction: AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma Clinical cancer research : an official journal of the American Association for Cancer Research
    Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, Saha S, Yang D, Gill PS, Lingen MW, Saloura V, Villaflor VM, Salgia R, Kimple RJ, Wheeler DL
    2018 Dec 1;24(23):6099. doi: 10.1158/1078-0432.CCR-18-3194.
  • HPV impacts survival of stage IVC non-oropharyngeal HNSCC cancer patients Otorhinolaryngology-head and neck surgery
    Burr AR, Harari PM, Ko HC, Chen S, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2018;3(1):10.15761/OHNS.1000160. doi: 10.15761/OHNS.1000160. Epub 2018 Feb 24.
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      OBJECTIVES: Human papillomavirus (HPV) status is a favorable prognostic marker for patients with oropharyngeal squamous cell carcinoma (OPSCC) and non-metastatic head and neck non-OPSCC. We evaluated the impact of HPV status on overall survival (OS) for patients with Stage IVC non-OPSCC.

      MATERIALS AND METHODS: Patients diagnosed with Stage IVC non-OPSCC and known HPV status between 2010-2013 were identified in the National Cancer Database. Univariate and multivariate analyses were performed to determine factors associated with OS. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in OS analyses. Multiple imputation method was used for sensitivity analysis.

      RESULTS: We identified 708 patients with Stage IVC non-OPSCC with 30% being HPV-positive. Unadjusted median survival was 10.3 months for HPV-negative patients and 21.4 months for HPV-positive patients (p<0.0001). Age ≥ 65 and tumor diameter were associated with worse OS (p<0.05) while treatment versus no treatment and HPV-positive status were associated with improved OS on multivariate analysis (p<0.001). Adjusted median survival for patients with HPV-negative and HPV-positive disease was 11.1 months and 23.8 months, respectively (p<0.001). On unadjusted subgroup analysis, patients with HPV-positive oral cavity disease exhibited improved outcomes (p<0.0001) while HPV-positive hypopharynx (p<0.06) and larynx (p<0.12) patients exhibited a trend for improved OS compared to HPV-negative patients. The survival advantage associated with HPV positivity was maintained on sensitivity analysis (p<0.01).

      CONCLUSION: These data demonstrate a clinically meaningful association between HPV status and OS in patients with non-OSPCC presenting with Stage IVC disease. In the absence of randomized data, these findings support active consideration of HPV status in clinical decision making, clinical trial design, and patient counseling regarding prognosis.

      PMID:30271885 | PMC:PMC6157736 | DOI:10.15761/OHNS.1000160


      View details for PubMedID 30271885
  • In Reply to Lin and Golden International journal of radiation oncology, biology, physics
    Jang S, Rosenberg SA, Bradley KA, Kimple RJ
    2018 Nov 1;102(3):672. doi: 10.1016/j.ijrobp.2018.06.043.
  • MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents Molecular cancer therapeutics
    McDaniel NK, Cummings CT, Iida M, Hülse J, Pearson HE, Vasileiadi E, Parker RE, Orbuch RA, Ondracek OJ, Welke NB, Kang GH, Davies KD, Wang X, Frye SV, Earp HS, Harari PM, Kimple RJ, DeRyckere D, Graham DK, Wheeler DL
    2018 Nov;17(11):2297-2308. doi: 10.1158/1535-7163.MCT-17-1239. Epub 2018 Aug 9.
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      The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.

      PMID:30093568 | PMC:PMC6215511 | DOI:10.1158/1535-7163.MCT-17-1239


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  • Results From 10 Years of a Free Oral Cancer Screening Clinic at a Major Academic Health Center International journal of radiation oncology, biology, physics
    Blitzer GC, Rosenberg SA, Anderson BM, McCulloch TM, Wieland AM, Hartig GK, Bruce JY, Witek ME, Kimple RJ, Harari PM
    2018 Sep 1;102(1):146-148. doi: 10.1016/j.ijrobp.2018.05.007. Epub 2018 Jul 3.
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      PMID:29980415 | PMC:PMC6089656 | DOI:10.1016/j.ijrobp.2018.05.007


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  • The Resident Individual Development Plan as a Guide for Radiation Oncology Mentorship International journal of radiation oncology, biology, physics
    Ko HC, Kimple RJ
    2018 Jul 15;101(4):786-788. doi: 10.1016/j.ijrobp.2018.02.153. Epub 2018 Mar 6.
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      PMID:29976489 | PMC:PMC6042972 | DOI:10.1016/j.ijrobp.2018.02.153


      View details for PubMedID 29976489
  • Beyond 'charting outcomes' in the radiation oncology match: analysis of self-reported applicant data Medical education online
    Jang S, Rosenberg SA, Hullett C, Bradley KA, Kimple RJ
    2018 Dec;23(1):1489691. doi: 10.1080/10872981.2018.1489691.
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      The Charting Outcomes resource is useful in gauging an applicant's competiveness for a given specialty. However, many variables are not reported in Charting Outcomes that may influence an applicant's ability to match. A significant proportion of applicants record their experiences in an anonymous, self-reported applicant spreadsheet. We analyzed factors associated with a successful match using this dataset to test the hypothesis that research productivity and high academic performance correlates with success rates. A retrospective analysis of "RadOnc Interview Spreadsheet" for the 2015, 2016, and 2017 radiation oncology match was performed. Data were accessed via studentdoctor.net. Board scores, research characteristics, Sub-I participation, and interview invitation rates were available. Mann-Whitney U, Kruskal-Wallis, and chi-square tests were used for statistical analysis. When possible, results were compared to those reported in the National Residency Match Program's "Charting Outcomes" report. A total of 158 applicants were examined for the applicant characteristics. Applicants applied to a median of 61 programs and received a median of 14 interviews. The mean step 1 score was 248 (range: 198 to 272) and most were in the highest grade point average quartile (68.3%). 21.7% participated in additional research year(s), and 19% obtained a PhD. The majority of applicants took three radiation oncology electives (48.7%). On multivariate analysis, alpha-omega-alpha (AOA) honors society status (p=0.033), participating in a research year (p=0.001) and number of journal publications (p=0.047) significantly correlated with higher interview invitation rates. In summary, this study identifies important considerations for radiation oncology applicants that have not been previously reported, such as induction into AOA and number of journal publications.

      PMID:29943670 | PMC:PMC6022246 | DOI:10.1080/10872981.2018.1489691


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  • Corrigendum: Potential role of the glycolytic oscillator in acute hypoxia in tumors (2015 &lt;i&gt;Phys. Med. Biol.&lt;/i&gt; 60 9215) Physics in medicine and biology
    Fru LC, Adamson EB, Campos DD, Fain SB, Jacques SL, Kogel vd, Nickel KP, Song C, Kimple RJ, Kissick MW
    2018 Jun 6. doi: 10.1088/1361-6560/aacaba. Online ahead of print.
    • More

      At the time of publication, our group had performed short tandem repeat (STR) testing on the SCC22B cell line and believed that had been correctly identified. As part of a recent comprehensive process to confirm the identity of cell lines in use in our lab, we repeated STR testing on all cell lines. These results were compared to the ExPASy Cellosaurus database (http://web.expasy.org/cellosaurus/). One cell line used in this manuscript was a near perfect match for T24 (CVCL_0554), a bladder carcinoma cell line commonly found as a cellular contaminant. Although we are unable to test the exact cells used in this manuscript, we believe that the cells labeled as SCC22B are most likely to actually be T24. The authors believe that neither the results nor the conclusions have been significantly changed on the basis of the specific cell line utilized.

      PMID:29873307 | DOI:10.1088/1361-6560/aacaba


      View details for PubMedID 29873307
  • In Reply to Hamstra International journal of radiation oncology, biology, physics
    Rosenberg SA, Bradley KA, Kimple RJ
    2018 Apr 1;100(5):1293-1294. doi: 10.1016/j.ijrobp.2018.01.038.
  • Identity Crisis - Rigor and Reproducibility in Human Cell Lines Radiation research
    Eckers JC, Swick AD, Kimple RJ
    2018 Jun;189(6):551-552. doi: 10.1667/RR15086.1. Epub 2018 Apr 13.
  • Genomics Reloaded: Rise of the Expression Profiles International journal of radiation oncology, biology, physics
    Gan GN, Kimple RJ
    2018 May 1;101(1):1-3. doi: 10.1016/j.ijrobp.2017.10.023.
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      PMID:29619961 | PMC:PMC6821516 | DOI:10.1016/j.ijrobp.2017.10.023


      View details for PubMedID 29619961
  • Impact of HPV Status on the Prognostic Potential of the AJCC Staging System for Larynx Cancer Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
    Davidson SM, Ko HC, Harari PM, Wieland AM, Chen S, Baschnagel AM, Kimple RJ, Witek ME
    2018 Sep;159(3):456-465. doi: 10.1177/0194599818766035. Epub 2018 Apr 3.
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      Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

      PMID:29611770 | PMC:PMC7141595 | DOI:10.1177/0194599818766035


      View details for PubMedID 29611770
  • Value of Elective Radiation Oncology Rotations: How Many Is Too Many? International journal of radiation oncology, biology, physics
    Jang S, Rosenberg SA, Hullet C, Bradley KA, Kimple RJ
    2018 Mar 1;100(3):558-559. doi: 10.1016/j.ijrobp.2017.10.052. Epub 2017 Nov 6.
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      PMID:29413271 | PMC:PMC5806148 | DOI:10.1016/j.ijrobp.2017.10.052


      View details for PubMedID 29413271
  • Primary intracranial leiomyosarcoma in an immunocompetent patient: Case report and review of the literature Clinical neurology and neurosurgery
    Gallagher SJ, Rosenberg SA, Francis D, Salamat S, Howard SP, Kimple RJ
    2018 Feb;165:76-80. doi: 10.1016/j.clineuro.2017.12.014. Epub 2018 Jan 6.
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      Primary leiomyosarcoma is a rare tumor in the CNS, with few reported cases. Here, we describe a case of a primary intracranial leiomyosarcoma of the tentorium cerebelli. A 43-year-old woman presented with headache, acute vision loss, and difficulty speaking. MRI revealed a large heterogeneous-enhancing occipital mass, which was subsequently resected and diagnosed as a primary intracranial leiomyosarcoma. The patient went onto adjuvant radiotherapy delivering 60 Gy in 30 fractions. These tumors are exceedingly rare in immunocompetent individuals. We reviewed the 16 cases that have been reported in the literature. Surgical resection was the most common treatment (92%) with 53% receiving adjuvant radiation. There currently is no standard treatment regimen for intracranial leiomyosarcomas. Additional case reports that include descriptive treatment approaches with patient outcomes may help ascertain the best approach to treating these malignancies.

      PMID:29324399 | DOI:10.1016/j.clineuro.2017.12.014


      View details for PubMedID 29324399
  • Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma Cell death & disease
    Redlich N, Robinson AM, Nickel KP, Stein AP, Wheeler DL, Adkins DR, Uppaluri R, Kimple RJ, Van Tine A, Michel LS
    2018 Jan 5;9(1):5. doi: 10.1038/s41419-017-0029-0.
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      ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.

      PMID:29305574 | PMC:PMC5849045 | DOI:10.1038/s41419-017-0029-0


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  • Biological characterization of a novel in vitro cell irradiator PloS one
    Fowler TL, Fisher MM, Bailey AM, Bednarz BP, Kimple RJ
    2017 Dec 12;12(12):e0189494. doi: 10.1371/journal.pone.0189494. eCollection 2017.
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      To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through γH2AX image cytometry. A high correlation between physical absorbed dose and biologic dose was seen for the production of intracellular reactive oxygen species, physical DNA double strand breaks, and modulation of the cellular double stand break pathway. The results compared favorably to irradiation with a traditional 137Cs source. The rapid, straightforward tests described form a reasonable approach for biologic characterization of novel irradiators. These additional testing metrics go beyond standard physics testing such as Monte Carlo simulation and thermo-luminescent dosimeter evaluation to confirm that a novel irradiator can produce the desired dose effects in vitro. Further, assessment of these biological metrics confirms that the physical handling of the cells during the irradiation process results in biologic effects that scale appropriately with dose.

      PMID:29232400 | PMC:PMC5726654 | DOI:10.1371/journal.pone.0189494


      View details for PubMedID 29232400
  • The Second Stain: A Viral Whodunnit International journal of radiation oncology, biology, physics
    Rosenberg SA, Kimple RJ
    2017 Dec 1;99(5):1061. doi: 10.1016/j.ijrobp.2017.05.027.
  • The Future of Radiobiology Journal of the National Cancer Institute
    Kirsch DG, Diehn M, Kesarwala AH, Maity A, Morgan MA, Schwarz JK, Bristow R, Demaria S, Eke I, Griffin RJ, Haas-Kogan D, Higgins GS, Kimmelman AC, Kimple RJ, Lombaert IM, Ma L, Marples B, Pajonk F, Park CC, Schaue D, Tran PT, Willers H, Wouters BG, Bernhard EJ
    2018 Apr 1;110(4):329-340. doi: 10.1093/jnci/djx231.
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      Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community.

      PMID:29126306 | PMC:PMC5928778 | DOI:10.1093/jnci/djx231


      View details for PubMedID 29126306
  • Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol Molecular cancer therapeutics
    Pearson HE, Iida M, Orbuch RA, McDaniel NK, Nickel KP, Kimple RJ, Arbiser JL, Wheeler DL
    2018 Jan;17(1):204-214. doi: 10.1158/1535-7163.MCT-17-0384. Epub 2017 Oct 20.
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      Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR.

      PMID:29054984 | PMC:PMC5752575 | DOI:10.1158/1535-7163.MCT-17-0384


      View details for PubMedID 29054984
  • Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx JAMA otolaryngology-- head & neck surgery
    Ko HC, Harari PM, Chen S, Wieland AM, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2017 Nov 1;143(11):1126-1133. doi: 10.1001/jamaoto.2017.1756.
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      IMPORTANCE: Radiotherapy (RT)-based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease.

      OBJECTIVE: To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches.

      DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer-accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017.

      INTERVENTIONS: Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy.

      MAIN OUTCOMES AND MEASURES: Five-year overall survival (OS).

      RESULTS: A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42).

      CONCLUSIONS AND RELEVANCE: Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

      PMID:29049434 | PMC:PMC5710357 | DOI:10.1001/jamaoto.2017.1756


      View details for PubMedID 29049434
  • Prognostic implications of human papillomavirus status for patients with non-oropharyngeal head and neck squamous cell carcinomas Journal of cancer research and clinical oncology
    Ko HC, Harari PM, Sacotte RM, Chen S, Wieland AM, Yu M, Baschnagel AM, Bruce JY, Kimple RJ, Witek ME
    2017 Nov;143(11):2341-2350. doi: 10.1007/s00432-017-2481-8. Epub 2017 Jul 27.
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      PURPOSE: We examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC).

      METHODS: Patients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis.

      RESULTS: We identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5 months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage <2, and N-stage ≥1. Unadjusted 3-year overall survival was 62% and 80% for HPV-negative and HPV-positive patients, respectively (p < 0.0001). On multivariate analysis, mortality was reduced for HPV-positive patients with early stage (HR = 0.68) and locally advanced disease (HR = 0.46). Adjusted 3-year overall survival was 65% for HPV-negative and 76% for HPV-positive patients (p < 0.0001). The survival advantage of HPV was maintained in all subsites and robust on sensitivity analysis.

      CONCLUSIONS: Patients with HPV-positive non-OPSCC exhibit similar characteristics as HPV-positive OPSCC. Overall survival was significantly higher for patients with HPV-positive versus HPV-negative non-OPSCC. These data reveal that HPV-positive non-OPSCC represent a favorable cohort that warrants recognition in the design of future clinical trial investigation.

      PMID:28752235 | PMC:PMC7069668 | DOI:10.1007/s00432-017-2481-8


      View details for PubMedID 28752235
  • Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition Clinical cancer research : an official journal of the American Association for Cancer Research
    Prabakaran PJ, Javaid AM, Swick AD, Werner LR, Nickel KP, Sampene E, Hu R, Ong IM, Bruce JY, Hartig GK, Wieland AM, Canon J, Harari PM, Kimple RJ
    2017 Oct 15;23(20):6044-6053. doi: 10.1158/1078-0432.CCR-17-0969. Epub 2017 Jun 28.
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      Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044-53. ©2017 AACR.

      PMID:28659312 | PMC:PMC5641244 | DOI:10.1158/1078-0432.CCR-17-0969


      View details for PubMedID 28659312
  • Small cell carcinoma of the head and neck: An analysis of the National Cancer Database Oral oncology
    Pointer KB, Ko HC, Brower JV, Witek ME, Kimple RJ, Lloyd RV, Harari PM, Baschnagel AM
    2017 Jun;69:92-98. doi: 10.1016/j.oraloncology.2017.04.009. Epub 2017 Apr 25.
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      PURPOSE/OBJECTIVE(S): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region.

      MATERIALS/METHODS: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival.

      RESULTS: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14).

      CONCLUSIONS: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease.

      PMID:28559027 | PMC:PMC5553627 | DOI:10.1016/j.oraloncology.2017.04.009


      View details for PubMedID 28559027
  • Clinical Outcomes and Prognostic Factors of Adenoid Cystic Carcinoma of the Head and Neck Anticancer research
    Jang S, Patel PN, Kimple RJ, McCulloch TM
    2017 Jun;37(6):3045-3052. doi: 10.21873/anticanres.11659.
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      BACKGROUND: Adenoid cystic carcinoma (ACC) is a salivary gland malignancy with unpredictable growth and poorly understood prognostic factors.

      PATIENTS AND METHODS: A database search of patients treated at a single Institution was used to identify patients with histologically-confirmed ACC. Patient, tumor, and treatment characteristics were examined via review of medical records.

      RESULTS: Overall survival of 70 patients identified at 5, 10, and 15 years was 80.4%, 61.3%, and 29.4%, respectively. Disease recurrence was seen in 31.9%; of these, 72.7% developed distant metastasis. Older age, higher stage, skull base involvement, positive margins, and metastatic disease, but not local recurrence, predicted a worse overall survival. Higher stage and skull base disease were also associated with shorter disease-free survival. While lung metastasis was the most common, vertebral metastasis was associated with poorer survival.

      CONCLUSION: Disease stage, positive margins, skull base involvement, perineural invasion, time to recurrence, and location of metastasis, but not nodal involvement, could serve as poor prognostic factors in ACC.

      PMID:28551643 | PMC:PMC7238770 | DOI:10.21873/anticanres.11659


      View details for PubMedID 28551643
  • Potential Mechanisms of Vascular Thrombosis after Microwave Ablation in an in Vivo Liver Journal of vascular and interventional radiology : JVIR
    Chiang J, Nickel K, Kimple RJ, Brace CL
    2017 Jul;28(7):1053-1058. doi: 10.1016/j.jvir.2017.03.034. Epub 2017 Apr 26.
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      PURPOSE: To evaluate potential biologic and thermal mechanisms of the observed differences in thrombosis rates between hepatic vessels during microwave (MW) ablation procedures.

      MATERIALS AND METHODS: MW ablation antennae were placed in single liver lobes of 2 in vivo porcine liver models (n = 3 in each animal; N = 6 total) in the proximity of a large (> 5 mm) portal vein (PV) and hepatic veins (HVs). Each ablation was performed with 100 W for 5 minutes. Conventional ultrasound imaging and intravascular temperature probes were used to evaluate vessel patency and temperature changes during the ablation procedure. Vascular endothelium was harvested 1 hour after ablation and used to characterize genes and proteins associated with thrombosis in PVs and HVs.

      RESULTS: Targeted PVs within the MW ablation zone exhibited thrombosis at a significantly higher rate than HVs (54.5% vs 0.0%; P = .0046). There was a negligible change in intravascular temperature in PVs and HVs during the ablation procedure (0.2°C ± 0.4 vs 0.6°C ± 0.9; P = .46). PVs exhibited significantly higher gene expression than HVs in terms of fold differences in thrombomodulin (2.9 ± 2.0; P = .0001), von Willebrand factor (vWF; 7.6 ± 1.5; P = .0001), endothelial protein C receptor (3.50 ± 0.49; P = .0011), and plasminogen activator inhibitor (1.46 ± 0.05; P = .0014). Western blot analysis showed significantly higher expression of vWF (2.32 ± 0.92; P = .031) in PVs compared with HVs.

      CONCLUSIONS: Large PVs exhibit thrombosis more frequently than HVs during MW ablation procedures. Biologic differences in thrombogenicity, rather than heat transfer, between PVs and HVs may contribute to their different rates of thrombosis.

      PMID:28456355 | PMC:PMC5483190 | DOI:10.1016/j.jvir.2017.03.034


      View details for PubMedID 28456355
  • Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC Molecular cancer therapeutics
    Swick AD, Prabakaran PJ, Miller MC, Javaid AM, Fisher MM, Sampene E, Ong IM, Hu R, Iida M, Nickel KP, Bruce JY, Wheeler DL, Kimple RJ
    2017 Jul;16(7):1257-1268. doi: 10.1158/1535-7163.MCT-17-0115. Epub 2017 Apr 26.
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      Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.

      PMID:28446642 | PMC:PMC5505754 | DOI:10.1158/1535-7163.MCT-17-0115


      View details for PubMedID 28446642
  • The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor Science signaling
    Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, Stein AP, Salgia R, Rolff J, Kimple RJ, Wheeler DL
    2017 Jan 3;10(460):eaag1064. doi: 10.1126/scisignal.aag1064.
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      The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.

      PMID:28049763 | PMC:PMC7094775 | DOI:10.1126/scisignal.aag1064


      View details for PubMedID 28049763
  • Defining the boundaries and expanding the utility of head and neck cancer patient derived xenografts Oral oncology
    Swick AD, Stein AP, McCulloch TM, Hartig GK, Ong IM, Sampene E, Prabakaran PJ, Liu CZ, Kimple RJ
    2017 Jan;64:65-72. doi: 10.1016/j.oraloncology.2016.11.017. Epub 2016 Dec 8.
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      BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system.

      METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach.

      RESULTS: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft.

      CONCLUSIONS: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation.

      PMID:28024726 | PMC:PMC5218527 | DOI:10.1016/j.oraloncology.2016.11.017


      View details for PubMedID 28024726
  • AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma Clinical cancer research : an official journal of the American Association for Cancer Research
    Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, Saha S, Yang D, Gill PS, Lingen MW, Saloura V, Villaflor VM, Salgia R, Kimple RJ, Wheeler DL
    2015 Jun 1;21(11):2601-12. doi: 10.1158/1078-0432.CCR-14-2648. Epub 2015 Mar 12.
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      PURPOSE: Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical.

      EXPERIMENTAL DESIGN: In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC.

      RESULTS: AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance.

      CONCLUSIONS: This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.

      PMID:25767293 | PMC:PMC5032632 | DOI:10.1158/1078-0432.CCR-14-2648


      View details for PubMedID 25767293
  • Influence of handling conditions on the establishment and propagation of head and neck cancer patient derived xenografts PloS one
    Stein AP, Saha S, Liu CZ, Hartig GK, Lambert PF, Kimple RJ
    2014 Jun 26;9(6):e100995. doi: 10.1371/journal.pone.0100995. eCollection 2014.
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      BACKGROUND: Patient derived xenografts (PDXs) for head and neck cancer (HNC) and other cancers represent powerful research platforms. Most groups implant patient tissue into immunodeficient mice immediately although the significance of this time interval is anecdotal. We tested the hypothesis that the time from tumor excision to implantation is crucial for PDX passaging and establishment.

      METHODS: We examined whether time or storage medium affected PDX viability for passaging two established HNC PDXs (UW-SCC34, UW-SCC52). Tumors were harvested, stored in ice-cold media or saline for 0-48 hours, and implanted into new mice. Tumor growth was compared by two-way ANOVA with respect to time and storage condition. Three new HNC PDXs (UW-SCC63-65) were generated by implanting patient tissue into mice immediately (Time 0) and 24 hours after receiving tissue from the operating room.

      RESULTS: Similar quantities of tumor were implanted into each mouse. At the end of the experiment, no significant difference was seen in mean tumor weight between the media and saline storage conditions for UW-SCC34 or UW-SCC52 (p = 0.650 and p = 0.177, respectively). No difference in tumor formation prevalence was seen on the basis of time from harvest to implantation (≥13 of 16 tumors grew at every time point). Histological analysis showed strong similarity to the initial tumor across all groups. Tumors developed at both Time 0 and 24 hours for UW-SCC63 and UW-SCC64.

      CONCLUSIONS: We demonstrated that neither storage medium nor time from tumor excision to implantation (up to 48 hours) affected viability or histological differentiation in a subsequent passage for two HNC PDXs. Moreover, we revealed that fresh patient tissue is viable up to 24 hours post-resection. This information is important as it applies to the development and sharing of PDXs.

      PMID:24967635 | PMC:PMC4072729 | DOI:10.1371/journal.pone.0100995


      View details for PubMedID 24967635
  • Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts Clinical cancer research : an official journal of the American Association for Cancer Research
    Kimple RJ, Harari PM, Torres AD, Yang RZ, Soriano BJ, Yu M, Armstrong EA, Blitzer GC, Smith MA, Lorenz LD, Lee D, Yang DT, McCulloch TM, Hartig GK, Lambert PF
    2013 Feb 15;19(4):855-64. doi: 10.1158/1078-0432.CCR-12-2746. Epub 2012 Dec 18.
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      PURPOSE: To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient tumorgraft model of human papillomavirus (HPV)-positive and HPV-negative cancers.

      EXPERIMENTAL DESIGN: Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin-embedded as well as flash-frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity.

      RESULTS: Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations P = 0.085 and P = 0.002, respectively). Significant growth inhibition of representative tumorgrafts was shown with cisplatin, cetuximab, or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain.

      CONCLUSIONS: We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.

      PMID:23251001 | PMC:PMC3581858 | DOI:10.1158/1078-0432.CCR-12-2746


      View details for PubMedID 23251001

Contact Information

Randall Kimple, MD, PhD

1111 Highland Avenue,
3107 WIMR
Madison, WI 53705-2275