Zachary Morris headshot

Zachary Morris, MD, PhD

Assistant Professor

Department of Human Oncology

I am an assistant professor and vice chair of the Department of Human Oncology. I am originally from Rockford, Ill., and completed my undergraduate studies at Ripon College in Ripon, Wis. After my undergraduate work, I earned two Master’s degrees (Medical Anthropology and History of Science, Medicine, and Technology) at Oxford University as a Rhodes Scholar. I completed my MD at Harvard Medical School and my PhD at Harvard University in the Biological and Biomedical Sciences Program, where I performed thesis research in the laboratory of Prof. Andrea McClatchey.

I completed a preliminary year internship in internal medicine at the University of Hawaii and then completed my residency training in radiation oncology at the University of Wisconsin Hospitals and Clinics. Under the American Board of Radiology’s Holman Pathway, I spearheaded a collaborative research project during my residency in the labs of Prof. Paul Sondel and Prof. Paul Harari.

As a physician-scientist, my current clinical focus is on the treatment of patients with melanoma and soft tissue sarcomas. My independent translational research laboratory focuses on the mechanisms whereby radiation may enhance the response to immunotherapies. I serve as program director for the University of Wisconsin Bentson Research Fellowship and am an active member of ASTRO, ASCO, RSNA, ABS, ACR, AACR, Radiation Research Society, the Society for Immunotherapy in Cancer (SITC) and the NCCN Guidelines expert panel on soft tissue sarcomas.


Resident, University of Wisconsin–Madison, Radiation Oncology (2016)

Intern, University of Hawaii, Internal Medicine (2012)

MD, Harvard Medical School, Medicine (2011)

PhD, Harvard University, Biological and Biomedical Sciences (2011)

MSc, Oxford University, History of Science, Medicine and Technology (2004)

MSc, Oxford University, Medical Anthropology (2003)

BA, Ripon College, Chemistry and Biology (2002)

Academic Appointments

Vice Chair, Human Oncology (2018)

Program Director, Bentson Translational Research Fellowship, Human Oncology (2017)

Assistant Professor, Human Oncology (2016)

Selected Honors and Awards

The Ride Scholar Award, University of Wisconsin (2016)

Outstanding Young Investigator, Immuno-Oncology Young Investigator’s Forum (2015)

Resident Seed Grant Recipient, American Society for Radiation Oncology (ASTRO) (2014)

Research Resident Grant Recipient, Radiological Society of North America (RSNA) (2013)

Intern of the Year, University of Hawaii Internal Medicine Residency Program (2012)

Albert Schweitzer Fellow (Boston) (2005)

Rhodes Scholar (Wisconsin & Wadham) (2002)

Senator Barry M. Goldwater Scholarship   (2001)

Wisconsin Independent College Foundation Rath Scholarship  (2001)

U.S. Department of Energy, Energy Research Undergraduate Fellowship (2000)

Boards, Advisory Committees and Professional Organizations

Big Ten Cancer Research Consortium Head and Neck Working Group (2017–pres.)

American College of Radiology (ACR), Radiation Oncology Commission Young Physician Section Chair (2017–pres.)

American College of Radiology (ACR), Journal Advisor, Radiobiology Expert Editor (2017–pres.)

American Brachytherapy Society Member (2016–pres.)

American Brachytherapy Society International Committee Task Group Co-Chair (2016–pres.)

National Cancer Center Network (NCCN) Member (2016–pres.)

National Cancer Center Network (NCCN) Soft Tissue Sarcoma Expert Panel Member (2016–pres.)

University of Wisconsin Institute for Clinical and Translational Research (2016–pres.)

American Society for Radiation Oncology (ASTRO), State Captain (2016–pres.)

ASTRO Annual Meeting Scientific/Education Programing Abstract Reviewer (2016–pres.)

Radiation Research Society, Sponsored Faculty Member (2016–pres.)

American Academy of Cancer Research (AACR) Member (2016–pres.)

ASTRO Annual Meeting Scientific Committee Member (2015–pres.)

ASTRO Community of Radiation Oncology Physician Scientists (CROPS) (2015–pres.)

ASTRO International Education Subcommittee Member (2015–pres.)

American College of Radiology (ACR) Journal Advisor, ARRO Guest Editor (2015–pres.)

Society for Immunotherapy in Cancer (SITC) Early Career Scientist Committee Member (2015–2016)

American College of Radiology (ACR) Resident and Fellow Section International Outreach Subcommittee Member (2015–2016)

Association of Residents in Radiation Oncology (ARRO) Executive Committee (Elected) (2014–2016)

American Society for Radiation Oncology (ASTRO) Member (2012–pres.)

Association of Residents in Radiation Oncology (ARRO) Co-chair, Global Health Subcommittee (2014–2016)

Association of Residents in Radiation Oncology (ARRO) Director, Mutual Mentorship Program (2014–2016)

Association of Residents in Radiation Oncology (ARRO) Founder and Director, Global Health Rotation Initiative (2014–2016)

Society for Immunotherapy in Cancer (SITC) Member (2013–pres.)

American Society for Clinical Oncology (ASCO) Member (2012–pres.)

Radiological Society of North America (RSNA) Member (2012–pres.)

American College of Radiology (ACR) Member (2012–pres.)

Research Focus

Radiation therapy, Immunotherapy, Melanoma, Sarcoma, Head and Neck Cancer

Radiation may augment the local and systemic anti-tumor immune response to cancer immunotherapies.

In the Morris Lab, we are focused on using preclinical and translational research approaches to study the mechanisms whereby radiation may impact the anti-tumor response to immunotherapies. Our primary objective is to determine whether and how radiation may optimally be employed to simultaneously modulate the tumor immune microenvironment and to increase the susceptibility of tumor cells to immune response. We seek to test these approaches in early phase clinical studies where they may be further refined with the ultimate aim of improving survival and achieving cures in patients with metastatic cancers.

In Situ Tumor Vaccination

In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient’s own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an anti-tumor T cell response. Radiation therapy elicits an anti-tumor effect through induction of DNA damage in tumor cells, yet it has long been recognized that host immune capability and tumor immune susceptibility modulate the sensitivity of a tumor to radiation. The mechanisms by which local radiation may interact with the immune system include release of tumor-specific antigens, phenotypic changes in tumor cell expression of immune susceptibility markers and local eradication of suppressive immune cell lineages. By modulating tumor immune tolerance and functional immunogenicity at a targeted site, radiation may serve as a method of in situ tumor vaccination. Multiple preclinical studies demonstrate that random tumor-specific protein mutations are among the most immunogenic tumor antigens recognized by T cells. By rendering such antigens accessible to immune recognition, radiation may augment the local and systemic anti-tumor response to immunotherapy. If proven effective, such combinations might transform RT from a predominantly loco-regional treatment to a critical component of systemic therapy.

Graph showing In situ vaccination with radiation and intra-tumor injection of immunocytokine improved survival and control of metastatic disease when combined with T cell checkpoint blockade
In situ vaccination with radiation and intra-tumor injection of immunocytokine improved survival and control of metastatic disease when combined with T cell checkpoint blockade

Relevant publications


Morris ZS, Guy EI, Francis DM, Gressett MM, Werner LR, Carmichael LL, Yang LL, Armstrong EA, Huang S, Navid JAF, Gillies SD, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Research. 2016 Jul 1;76(13):3929-41. PMID: 27197149.



  1. NIH Director’s Early Independence Award (DP5) 9/2017– 8/2022. Combining radiation and tumor-specific antibody therapies to elicit in situ vaccination. Role: Principal Investigator
  2. UWCCC Tumor Immunology/Cancer Immunotherapy Pilot Award 7/2017 – 6/2018. In situ vaccination to redress clinical challenges in the treatment of metastatic melanoma. Role: Principal Investigator (Morris, Kuo)

Effects of Radiation on Tumor Cell Immune Susceptibility

Prior studies have consistently demonstrated phenotypic upregulation of FAS and MHC-I following radiation therapy, and recent studies have suggested mechanisms whereby radiation may influence tumor expression of the checkpoint ligand, PD-L1. The time course, potentially shared underlying mechanisms and the possibility of a broader impact of radiation on expression of other phenotypic markers of tumor immune susceptibility remain to be clarified. Given the potential capacity of radiation to synergize with immunotherapies, it is vital to understand not only how radiation may affect tumor cell susceptibility to immune response but also to define the time course and mechanism of such effects.

chart showing effects of radiation on tumor cell immune susceptibility

Relevant publications


Werner LR, Kler JS, Gressett MM, Riegert M, Werner LK, Heinze CM, Kern JG, Abbariki M, Erbe AK, Patel RB, Sriramaneni RN, Harari PM, Morris ZS. Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. Radiother Oncol. 2017 Sep 8. pii: S0167-8140(17)32526-4. PMID: 28893414.



  1. NIH Director’s Early Independence Award (DP5) 9/2017–8/2022. Combining radiation and tumor-specific antibody therapies to elicit in situ vaccination. Role: Principal Investigator

Development of new models and methods for testing novel combinations of radiation with immunotherapy

In a series of “next generation” studies, we are developing novel tumor models that will enable us to better test the efficacy of combinations of radiation with immunotherapies. At the same time, we are also exploring new methods for evaluating the mechanisms of interaction between these treatment modalities. In addition, we are actively exploring multiple unique approaches to optimizing this cooperative interaction through novel combinations of distinct radiotherapy modalities with diverse immunotherapies.

illustration of selected mechanisms of interaction between radiation and immunotherapy
Selected mechanisms of interaction between radiation and immunotherapy


  1. Wisconsin Alumni Research Foundation 20/20 Award 10/2016–9/2018. Combining molecular targeted radiation with antitumor mAb and IL2 to create a potent in situ cancer vaccine. Role: Co-Principal Investigator (Sondel, Morris, Weichert, Bednarz, Otto)
  2. The Ride Scholars 1/2017–12/2017. Pilot investigation of novel combinations of molecular targeted immunotherapy with radiation. Role: Principal Investigator
  3. UWCCC Tumor Microenvironment Pilot Award 7/2017– 6/2018. Development of patient-derived xenografts in humanized mice. Role: Co-Principal Investigator (Kimple, Morris)
  4. RSNA Fellows Research Award 7/2017–6/2018. Utilization of Radiotherapy to Enhance the Efficacy of Systemic Dual Checkpoint Inhibition in Preclinical Metastatic Cancer Models. Role: Scientific Mentor for Ravi Patel
  5. UWCCC Tumor Immunology/Cancer Immunotherapy Pilot Award 7/2017–6/2018. In situ vaccination to redress clinical challenges in the treatment of metastatic melanoma. Role: Principal Investigator (Morris, Kuo)
  6. UW H&N SPORE Career Enhancement Program Award 7/2017–6/2018. Development of syngeneic murine head and neck squamous cell carcinoma tumor models for testing in situ tumor vaccination therapeutic approaches. Role: Principal Investigator

Early phase clinical trial development and correlative studies

As a physician-scientist, I help lead early phase clinical research efforts aimed at translating findings from our preclinical research to the clinic in order to improve treatment of cancer patients. We are currently advancing early phase clinical studies involving a variety of disease sites with the goal of improving clinical outcomes and cure rates for patients with cancer. Correlative biomarker studies and tissue samples from these clinical studies will be instrumental in allowing us to test the translational relevance of our preclinical findings, and this should enable us to refine our approaches to achieve greater clinical effect.


University of Wisconsin Hospitals and Clinics



As a physician-scientist, I help lead early phase clinical research efforts aimed at translating findings from our preclinical research to the clinic in order to improve treatment of cancer patients. We are currently advancing early phase clinical studies involving a variety of different disease sites with the goal of improving clinical outcomes and cure rates for patients with cancer. Correlative biomarker studies and tissue samples from these clinical studies will be instrumental in allowing us to test the translational relevance of our preclinical findings and this should enable us to refine our approaches to achieve greater clinical effect.

  • Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. J Immunother Cancer
    Voeller J, Erbe AK, Slowinski J, Rasmussen K, Carlson PM, Hoefges A, VandenHeuvel S, Stuckwisch A, Wang X, Gillies SD, Patel RB, Farrel A, Rokita JL, Maris J, Hank JA, Morris ZS, Rakhmilevich AL, Sondel PM
    2019 Dec 06; 7 (1): 344
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      BACKGROUND: Unlike some adult cancers, most pediatric cancers are considered immunologically cold and generally less responsive to immunotherapy. While immunotherapy has already been incorporated into standard of care treatment for pediatric patients with high-risk neuroblastoma, overall survival remains poor. In a mouse melanoma model, we found that radiation and tumor-specific immunocytokine generate an in situ vaccination response in syngeneic mice bearing large tumors. Here, we tested whether a novel immunotherapeutic approach utilizing radiation and immunocytokine together with innate immune stimulation could generate a potent antitumor response with immunologic memory against syngeneic murine neuroblastoma.

      METHODS: Mice bearing disialoganglioside (GD2)-expressing neuroblastoma tumors (either NXS2 or 9464D-GD2) were treated with radiation and immunotherapy (including anti-GD2 immunocytokine with or without anti-CTLA-4, CpG and anti-CD40 monoclonal antibody). Tumor growth, animal survival and immune cell infiltrate were analyzed in the tumor microenvironment in response to various treatment regimens.

      RESULTS: NXS2 had a moderate tumor mutation burden (TMB) while N-MYC driven 9464D-GD2 had a low TMB, therefore the latter served as a better model for high-risk neuroblastoma (an immunologically cold tumor). Radiation and immunocytokine induced a potent in situ vaccination response against NXS2 tumors, but not in the 9464D-GD2 tumor model. Addition of checkpoint blockade with anti-CTLA-4 was not effective alone against 9464D-GD2 tumors; inclusion of CpG and anti-CD40 achieved a potent antitumor response with decreased T regulatory cells within the tumors and induction of immunologic memory.

      CONCLUSIONS: These data suggest that a combined innate and adaptive immunotherapeutic approach can be effective against immunologically cold syngeneic murine neuroblastoma. Further testing is needed to determine how these concepts might translate into development of more effective immunotherapeutic approaches for the treatment of clinically high-risk neuroblastoma.

      View details for PubMedID 31810498
  • Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial-Membrane-Coated Nanoparticles. Adv Mater
    Patel RB, Ye M, Carlson PM, Jaquish A, Zangl L, Ma B, Wang Y, Arthur I, Xie R, Brown RJ, Wang X, Sriramaneni R, Kim K, Gong S, Morris ZS
    2019 Sep 16; : e1902626
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      Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically "cold" tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These "cold" tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of "cold" tumors, resulting in a more diversified antitumor T-cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane-coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T-cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor-specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off-the-shelf therapeutics.

      View details for PubMedID 31523868
  • Heterochronic shifts and conserved embryonic shape underlie crocodylian craniofacial disparity and convergence. Proc Biol Sci
    Morris ZS, Vliet KA, Abzhanov A, Pierce SE
    2019 Feb 27; 286 (1897): 20182389
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      The distinctive anatomy of the crocodylian skull is intimately linked with dietary ecology, resulting in repeated convergence on blunt- and slender-snouted ecomorphs. These evolutionary shifts depend upon modifications of the developmental processes which direct growth and morphogenesis. Here we examine the evolution of cranial ontogenetic trajectories to shed light on the mechanisms underlying convergent snout evolution. We use geometric morphometrics to quantify skeletogenesis in an evolutionary context and reconstruct ancestral patterns of ontogenetic allometry to understand the developmental drivers of craniofacial diversity within Crocodylia. Our analyses uncovered a conserved embryonic region of morphospace (CER) shared by all non-gavialid crocodylians regardless of their eventual adult ecomorph. This observation suggests the presence of conserved developmental processes during early development (before Ferguson stage 20) across most of Crocodylia. Ancestral state reconstruction of ontogenetic trajectories revealed heterochrony, developmental constraint, and developmental systems drift have all played essential roles in the evolution of ecomorphs. Based on these observations, we conclude that two separate, but interconnected, developmental programmes controlling craniofacial morphogenesis and growth enabled the evolutionary plasticity of skull shape in crocodylians.

      View details for PubMedID 30963831
  • Preclinical Characterization of 86/90Y-NM600 in a variety of murine and human cancer tumor models. J Nucl Med
    Grudzinski JJ, Hernandez R, Marsh I, Patel R, Aluicio-Sarduy E, Engle J, Morris Z, Bednarz B, Weichert JP
    2019 Apr 06; :
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      We characterize the in vivo biodistribution and tumor selectivity of 86Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Methods: Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously (IV) with 9.25 MBq of 86Y-NM600 and imaged longitudinally over 4-5 days using microPET/CT. Percent injected activity per gram (%IA/g) for each volume-of-interest (VOI) was measured at each time point for the organs of interest. Mice were euthanized after the final time point and the tumor and organs of interest were counted with an automatic gamma counter. Absorbed doses delivered by 90Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of 90Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared to an equivalent absorbed dose delivered via external beam radiotherapy (XRT) using tumor volume as a measure of response. Histology and complete blood counts (CBC) were analyzed in naïve C57BL/6 mice who were injected with 9.25 MBq of 90Y-NM600 at 5, 10, and 28 days post injection (p.i.). Results: PET imaging showed consistent tumor accumulation and retention across all tumor models investigated with little off-target retention of NM600 except for in the liver, which is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66%IA/g (n = 3) and 9.10 ± 0.13 %IA/g (n = 3), respectively, at approximately 40-48 hr post injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematological parameters was transient when observed, returning to pre-therapy levels after 28 days. Conclusion: NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image guided TRT and combination with immunotherapies.

      View details for PubMedID 30954941
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy
    Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS
    2019 Mar - Apr; 18 (2): 240
  • 90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin's Lymphoma. Commun Biol
    Hernandez R, Walker KL, Grudzinski JJ, Aluicio-Sarduy E, Patel R, Zahm CD, Pinchuk AN, Massey CF, Bitton AN, Brown RJ, Sondel PM, Morris ZS, Engle JW, Capitini CM, Weichert JP
    2019; 2: 79
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      Finding improved therapeutic strategies against T-cell Non-Hodgkin's Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for targeted radionuclide therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease.

      View details for PubMedID 30820474
  • International Survey on the Use of Complementary and Alternative Medicines for Common Toxicities of Radiation Therapy. Adv Radiat Oncol
    Lee A, Kuczmarska-Haas A, Macomber MW, Woo K, Freese C, Morris ZS
    2019 Jan-Mar; 4 (1): 134-141
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      Purpose: Complementary and alternative medicines (CAMs) are widely used by patients with cancer. However, little is known about the extent to which these potential remedies are used internationally to treat the most common toxicities of radiation therapy. We report on the results of an international survey that assessed the use of CAMs.

      Methods and Materials: Surveys were distributed to 1174 practicing radiation oncologists. Questions evaluated the perceptions of CAMs and specific practice patterns for the use of CAM remedies in the treatment of common radiation-induced toxicities (eg, skin, fatigue, nausea, diarrhea, and mucositis/xerostomia). The responses were compared between the groups using the χ2 test and stratified on the basis of provider location, number of years in practice, and perception of CAMs.

      Results: A total of 114 radiation oncologists from 29 different countries completed the survey, with a balanced distribution between North American (n = 56) and non-North American (n = 58) providers. Among the responding clinicians, 63% recommended CAMs in their practice. The proportion of clinicians who recommend CAMs for radiation toxicities did not significantly vary when stratified by provider's number of years in practice (P = .23) or location (United States/Canada vs other; P = .74). Overall, providers reported that 29.4% of their patients use CAMs, and 87.7% reported that their practice encouraged or was neutral on CAM use, whereas 12.3% recommended stopping CAMs. The most common sources of patient information on CAMs were the Internet (75.4%), friends (60.5%), and family (58.8%). Clinicians reported the highest use of CAMs for radiation skin toxicity at 66.7%, followed by 48.2% for fatigue, 40.4% for nausea, and 36.8% for mucositis/xerostomia.

      Conclusions: Nearly two-thirds of the surveyed radiation oncologists recommend CAMs for radiation-related toxicities; however, they estimated that less than one third of patients use CAMs for this purpose. This suggests a need for further investigation and perhaps greater patient education on the roles of CAMs in treating radiation toxicities.

      View details for PubMedID 30706021
  • Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface. Genes Dev
    Chiasson-MacKenzie C, Morris ZS, Liu CH, Bradford WB, Koorman T, McClatchey AI
    2018 09 01; 32 (17-18): 1201-1214
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      The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability. We show that merlin deficiency primes the membrane:cytoskeleton interface for epidermal growth factor (EGF)-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. These changes profoundly alter EGF receptor (EGFR) trafficking in merlin-deficient cells, favoring increased membrane levels of its heterodimerization partner, ErbB2; clathrin-independent internalization; and recycling. Our work suggests that, unlike Ras transformed cells, merlin-deficient cells do not depend on macropinocytic protein scavenging and instead exploit macropinocytosis for receptor recycling. Finally, we provide evidence that the macropinocytic proficiency of NF2-deficient cells can be used for therapeutic uptake. This work provides new insight into fundamental mechanisms of macropinocytic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in NF2 mutant and other tumors.

      View details for PubMedID 30143526
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy
    Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS
    2018 Nov - Dec; 17 (6): 995-1003
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      As immunotherapies continue to emerge as a standard component of treatment for a variety of cancers, the imperative for testing these in combination with other standard cancer therapies grows. Radiation therapy may be a particularly well-suited partner for many immunotherapies. By modulating immune tolerance and functional immunogenicity at a targeted tumor site, radiation therapy may serve as a method of in situ tumor vaccination. In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an antitumor T cell response. The mechanisms whereby radiation may impact immunotherapy are diverse and include its capacity to simultaneously elicit local inflammation, temporary local depletion of suppressive lymphocyte lineages, enhanced tumor cell susceptibility to immune response, and immunogenic tumor cell death. Emerging data suggest that each of these mechanisms may display a distinct dose-response profile, making it challenging to maximize each of these effects using external beam radiation. Conversely, the highly heterogenous and conformal dose distribution achieved with brachytherapy may be optimal for enhancing the immunogenic capacity of radiation at a tumor site while minimizing off-target antagonistic effects on peripheral immune cells. Here, we review the immunogenic effects of radiation, summarize the clinical rationale and data supporting the use of radiation together with immunotherapies, and discuss the rationale and urgent need for further preclinical and clinical investigation specifically of brachytherapy in combination with immunotherapies. Harnessing these immunomodulatory effects of brachytherapy may offer solutions to overcome obstacles to the efficacy of immunotherapies in immunologically "cold" tumors while potentiating greater response in the context of immunologically "hot" tumors.

      View details for PubMedID 30078541
  • Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw
    von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Ganjoo KN, George S, Gonzalez RJ, Heslin MJ, Kane JM, Keedy V, Kim E, Koon H, Mayerson J, McCarter M, McGarry SV, Meyer C, Morris ZS, O'Donnell RJ, Pappo AS, Paz IB, Petersen IA, Pfeifer JD, Riedel RF, Ruo B, Schuetze S, Tap WD, Wayne JD, Bergman MA, Scavone JL
    2018 05; 16 (5): 536-563
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      Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for STS provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumors, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations.

      View details for PubMedID 29752328
  • Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites. Cancer Immunol Res
    Morris ZS, Guy EI, Werner LR, Carlson PM, Heinze CM, Kler JS, Busche SM, Jaquish AA, Sriramaneni RN, Carmichael LL, Loibner H, Gillies SD, Korman AJ, Erbe AK, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM
    2018 07; 6 (7): 825-834
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      In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

      View details for PubMedID 29748391
  • Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology. Lancet Oncol
    Bristow RG, Alexander B, Baumann M, Bratman SV, Brown JM, Camphausen K, Choyke P, Citrin D, Contessa JN, Dicker A, Kirsch DG, Krause M, Le QT, Milosevic M, Morris ZS, Sarkaria JN, Sondel PM, Tran PT, Wilson GD, Willers H, Wong RKS, Harari PM
    2018 05; 19 (5): e240-e251
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      The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents.

      View details for PubMedID 29726389
  • The skull roof tracks the brain during the evolution and development of reptiles including birds. Nat Ecol Evol
    Fabbri M, Mongiardino Koch N, Pritchard AC, Hanson M, Hoffman E, Bever GS, Balanoff AM, Morris ZS, Field DJ, Camacho J, Rowe TB, Norell MA, Smith RM, Abzhanov A, Bhullar BS
    2017 Oct; 1 (10): 1543-1550
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      Major transformations in brain size and proportions, such as the enlargement of the brain during the evolution of birds, are accompanied by profound modifications to the skull roof. However, the hypothesis of concerted evolution of shape between brain and skull roof over major phylogenetic transitions, and in particular of an ontogenetic relationship between specific regions of the brain and the skull roof, has never been formally tested. We performed 3D morphometric analyses to examine the deep history of brain and skull-roof morphology in Reptilia, focusing on changes during the well-documented transition from early reptiles through archosauromorphs, including nonavian dinosaurs, to birds. Non-avialan taxa cluster tightly together in morphospace, whereas Archaeopteryx and crown birds occupy a separate region. There is a one-to-one correspondence between the forebrain and frontal bone and the midbrain and parietal bone. Furthermore, the position of the forebrain-midbrain boundary correlates significantly with the position of the frontoparietal suture across the phylogenetic breadth of Reptilia and during the ontogeny of individual taxa. Conservation of position and identity in the skull roof is apparent, and there is no support for previous hypotheses that the avian parietal is a transformed postparietal. The correlation and apparent developmental link between regions of the brain and bony skull elements are likely to be ancestral to Tetrapoda and may be fundamental to all of Osteichthyes, coeval with the origin of the dermatocranium.

      View details for PubMedID 29185519
  • Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. Radiother Oncol
    Werner LR, Kler JS, Gressett MM, Riegert M, Werner LK, Heinze CM, Kern JG, Abbariki M, Erbe AK, Patel RB, Sriramaneni RN, Harari PM, Morris ZS
    2017 Sep; 124 (3): 418-426
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      BACKGROUND AND PURPOSE: We recently reported a time-sensitive, cooperative, anti-tumor effect elicited by radiation (RT) and intra-tumoral-immunocytokine injection in vivo. We hypothesized that RT triggers transcriptional-mediated changes in tumor expression of immune susceptibility markers at delayed time points, which may explain these previously observed time-dependent effects.

      MATERIALS AND METHODS: We examined the time course of changes in expression of immune susceptibility markers following in vitro or in vivo RT in B78 murine melanoma and A375 human melanoma using flow cytometry, immunoblotting, and qPCR.

      RESULTS: Flow cytometry and immunoblot revealed time-dependent increases in expression of death receptors and T cell co-stimulatory/co-inhibitory ligands following RT in murine and human melanoma. Using high-throughput qPCR, we observed comparable time courses of RT-induced transcriptional upregulation for multiple immune susceptibility markers. We confirmed analogous changes in B78 tumors irradiated in vivo. We observed upregulated expression of DNA damage response markers days prior to changes in immune markers, whereas phosphorylation of the STAT1 transcription factor occurred concurrently with changes following RT.

      CONCLUSION: This study highlights time-dependent, transcription-mediated changes in tumor immune susceptibility marker expression following RT. These findings may help in the design of strategies to optimize sequencing of RT and immunotherapy in translational and clinical studies.

      View details for PubMedID 28893414
  • Bridging Innovation and Outreach to Overcome Global Gaps in Radiation Oncology Through Information and Communication Tools, Trainee Advancement, Engaging Industry, Attention to Ethical Challenges, and Political Advocacy. Semin Radiat Oncol
    Dad L, Royce TJ, Morris Z, Moran M, Pawlicki T, Khuntia D, Hardenbergh P, Cummings B, Mayr N, Hu K
    2017 Apr; 27 (2): 98-108
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      An evolving paradigm in global outreach in radiation oncology has been the implementation of a more region-specific, needs-based approach to help close the gap in radiation services to low- and middle-income countries through the use of innovative tools in information and communication technology. This report highlights 4 information and communication technology tools in action today: (1) the NCCN Framework for Resource Stratification of NCCN guidelines, (2) ASTRO e-Contouring, (3), and (4) We also render special consideration to matters related to global outreach that we believe require distinct attention to help us meet the goals established by the 2011 United Nations׳ Declaration on noncommunicable diseases: (1) trainee advancement toward careers in global health, (2) ethical challenges of international outreach, (3) critical importance of political advocacy, and (4) collaboration with Industry.

      View details for PubMedID 28325248
  • Supply and Demand for Radiation Oncology in the United States: A Resident Perspective. Int J Radiat Oncol Biol Phys
    Burt LM, Trifiletti DM, Nabavizadeh N, Katz LM, Morris ZS, Royce TJ
    2017 02 01; 97 (2): 225-227
  • Online patient information from radiation oncology departments is too complex for the general population. Pract Radiat Oncol
    Rosenberg SA, Francis DM, Hullet CR, Morris ZS, Brower JV, Anderson BM, Bradley KA, Bassetti MF, Kimple RJ
    2017 Jan - Feb; 7 (1): 57-62
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      PURPOSE: Nearly two-thirds of cancer patients seek information about their diagnosis online. We assessed the readability of online patient education materials found on academic radiation oncology department Web sites to determine whether they adhered to guidelines suggesting that information be presented at a sixth-grade reading level.

      METHODS AND MATERIALS: The Association of American Medical Colleges Web site was used to identify all academic radiation oncology departments in the United States. One-third of these department Web sites were selected for analysis using a random number generator. Both general information on radiation therapy and specific information regarding various radiation modalities were collected. To test the hypothesis that the readability of these online educational materials was written at the recommended grade level, a panel of 10 common readability tests was used. A composite grade level of readability was constructed using the 8 readability measures that provide a single grade-level output.

      RESULTS: A mean of 5605 words (range, 2058-12,837) from 30 department Web sites was collected. Using the composite grade level score, the overall mean readability level was determined to be 13.36 (12.83-13.89), corresponding to a collegiate reading level. This was significantly higher than the target sixth-grade reading level (middle school, t (29) = 27.41, P < .001).

      CONCLUSIONS: Online patient educational materials from academic radiation oncology Web sites are significantly more complex than recommended by the National Institutes of Health and the Department of Health and Human Services. To improve patients' comprehension of radiation therapy and its role in their treatment, our analysis suggests that the language used in online patient information should be simplified to communicate the information at a more appropriate level.

      View details for PubMedID 27663932
  • Readability of Online Patient Educational Resources Found on NCI-Designated Cancer Center Web Sites. J Natl Compr Canc Netw
    Rosenberg SA, Francis D, Hullett CR, Morris ZS, Fisher MM, Brower JV, Bradley KA, Anderson BM, Bassetti MF, Kimple RJ
    2016 Jun; 14 (6): 735-40
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      BACKGROUND: The NIH and Department of Health & Human Services recommend online patient information (OPI) be written at a sixth grade level. We used a panel of readability analyses to assess OPI from NCI-Designated Cancer Center (NCIDCC) Web sites.

      METHODS: was used to identify 68 NCIDCC Web sites from which we collected both general OPI and OPI specific to breast, prostate, lung, and colon cancers. This text was analyzed by 10 commonly used readability tests: the New Dale-Chall Readability Formula, Flesch Reading Ease scale, Flesch-Kinaid Grade Level, FORCAST scale, Fry Readability Graph, Simple Measure of Gobbledygook test, Gunning Frequency of Gobbledygook index, New Fog Count, Raygor Readability Estimate Graph, and Coleman-Liau Index. We tested the hypothesis that the readability of NCIDCC OPI was written at the sixth grade level. Secondary analyses were performed to compare readability of OPI between comprehensive and noncomprehensive centers, by region, and to OPI produced by the American Cancer Society (ACS).

      RESULTS: A mean of 30,507 words from 40 comprehensive and 18 noncomprehensive NCIDCCs was analyzed (7 nonclinical and 3 without appropriate OPI were excluded). Using a composite grade level score, the mean readability score of 12.46 (ie, college level: 95% CI, 12.13-12.79) was significantly greater than the target grade level of 6 (middle-school: P<.001). No difference between comprehensive and noncomprehensive centers was identified. Regional differences were identified in 4 of the 10 readability metrics (P<.05). ACS OPI provides easier language, at the seventh to ninth grade level, across all tests (P<.01).

      CONCLUSIONS: OPI from NCIDCC Web sites is more complex than recommended for the average patient.

      View details for PubMedID 27283166
  • Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer
    Morris ZS, Saha S, Magnuson WJ, Morris BA, Borkenhagen JF, Ching A, Hirose G, McMurry V, Francis DM, Harari PM, Chappell R, Tsuji S, Ritter MA
    2016 Aug 15; 122 (16): 2487-95
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      BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer.

      METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data.

      RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001).

      CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

      View details for PubMedID 27203227
  • In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Cancer Res
    Morris ZS, Guy EI, Francis DM, Gressett MM, Werner LR, Carmichael LL, Yang RK, Armstrong EA, Huang S, Navid F, Gillies SD, Korman A, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM
    2016 Jul 01; 76 (13): 3929-41
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      Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.

      View details for PubMedID 27197149
  • Results of the 2013-2015 Association of Residents in Radiation Oncology Survey of Chief Residents in the United States. Int J Radiat Oncol Biol Phys
    Nabavizadeh N, Burt LM, Mancini BR, Morris ZS, Walker AJ, Miller SM, Bhavsar S, Mohindra P, Kim MB, Kharofa J, ARRO Executive Committee
    2016 Feb 01; 94 (2): 228-34
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      PURPOSE: The purpose of this project was to survey radiation oncology chief residents to define their residency experience and readiness for independent practice.

      METHODS AND MATERIALS: During the academic years 2013 to 2014 and 2014 to 2015, the Association of Residents in Radiation Oncology (ARRO) conducted an electronic survey of post-graduate year-5 radiation oncology residents in the United States during the final 3 months of training. Descriptive statistics are reported.

      RESULTS: Sixty-six chief residents completed the survey in 2013 to 2014 (53% response rate), and 69 completed the survey in 2014 to 2015 (64% response rate). Forty to 85% percent of residents reported inadequate exposure to high-dose rate and low-dose rate brachytherapy. Nearly all residents in both years (>90%) reported adequate clinical experience for the following disease sites: breast, central nervous system, gastrointestinal, genitourinary, head and neck, and lung. However, as few as 56% reported adequate experience in lymphoma or pediatric malignancies. More than 90% of residents had participated in retrospective research projects, with 20% conducting resident-led prospective clinical trials and 50% conducting basic science or translational projects. Most chief residents reported working 60 or fewer hours per week in the clinical/hospital setting and performing fewer than 15 hours per week tasks that were considered to have little or no educational value. There was more than 80% compliance with Accreditation Council for Graduate Medical Education (ACGME) work hour limits. Fifty-five percent of graduating residents intended to join an established private practice group, compared to 25% who headed for academia. Residents perceive the job market to be more competitive than previous years.

      CONCLUSIONS: This first update of the ARRO chief resident survey since the 2007 to 2008 academic year documents US radiation oncology residents' experiences and conditions over a 2-year period. This analysis may serve as a valuable tool for those seeking to improve training of the next generation of oncology leaders.

      View details for PubMedID 26853332
  • Education and Training Needs in Radiation Oncology in India: Opportunities for Indo-US Collaborations. Int J Radiat Oncol Biol Phys
    Grover S, Chadha M, Rengan R, Williams TR, Morris ZS, Morgan DA, Tripuraneni P, Hu K, Viswanathan AN
    2015 Dec 01; 93 (5): 957-60
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      PURPOSE: To conduct a survey of radiation oncologists in India, to better understand specific educational needs of radiation oncology in India and define areas of collaboration with US institutions.

      METHODS AND MATERIALS: A 20-question survey was distributed to members of the Association of Indian Radiation Oncologists and the Indian Brachytherapy Society between November 2013 and May 2014.

      RESULTS: We received a total of 132 responses. Over 50% of the physicians treat more than 200 patients per day, use 2-dimensional or 3-dimensional treatment planning techniques, and approximately 50% use image guided techniques. For education needs, most respondents agreed that further education in intensity modulated radiation therapy, image guided radiation therapy, stereotactic radiation therapy, biostatistics, and research methods for medical residents would be useful areas of collaboration with institutions in the United States. Other areas of collaboration include developing a structured training module for nursing, physics training, and developing a second-opinion clinic for difficult cases with faculty in the United States.

      CONCLUSION: Various areas of potential collaboration in radiation oncology education were identified through this survey. These include the following: establishing education programs focused on current technology, facilitating exchange programs for trainees in India to the United States, promoting training in research methods, establishing training modules for physicists and oncology nurses, and creating an Indo-US. Tumor Board. It would require collaboration between the Association of Indian Radiation Oncologists and the American Society for Radiation Oncology to develop these educational initiatives.

      View details for PubMedID 26581132
  • NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol
    Chiasson-MacKenzie C, Morris ZS, Baca Q, Morris B, Coker JK, Mirchev R, Jensen AE, Carey T, Stott SL, Golan DE, McClatchey AI
    2015 Oct 26; 211 (2): 391-405
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      The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane-cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell-cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.

      View details for PubMedID 26483553
  • Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models. Clin Cancer Res
    Francis DM, Huang S, Armstrong EA, Werner LR, Hullett C, Li C, Morris ZS, Swick AD, Kragh M, Lantto J, Kimple RJ, Harari PM
    2016 Feb 01; 22 (3): 633-43
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      PURPOSE: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3.

      EXPERIMENTAL DESIGN: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor-resistant cell lines and xenografts.

      RESULTS: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone.

      CONCLUSIONS: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy.

      View details for PubMedID 26420857
  • Impact of a Contralateral Tumor Nodule on Survival in Non-Small-Cell Lung Cancer. J Thorac Oncol
    Morris ZS, Cannon DM, Morris BA, Bentzen SM, Kozak KR
    2015 Nov; 10 (11): 1608-15
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      INTRODUCTION: Contralateral lung tumors in non-small-cell lung cancer (NSCLC) are classified as stage M1a yet may represent hematogenous metastases or synchronous primary tumors. The impact of these tumors on overall survival (OS) is poorly understood. Here, we aim to determine whether NSCLC patients with M1a disease due only to a contralateral tumor nodule exhibit a favorable prognosis relative to other M1a or M1b patients.

      METHODS: Retrospective evaluation of the impact of contralateral tumor nodules on OS in NSCLC stratified by primary tumor size and N stage attained from Surveillance, Epidemiology, and End Results database.

      RESULTS: Of 173,640 patients, 5161 M1a-contra patients were identified. Median and 3-year OS for these patients exceeded that of patients with M1b (p < 0.0001) or other M1a disease (p < 0.0001). Primary tumor size and N stage were strongly associated with OS in M1a-contra patients. Three-year OS demonstrated a delayed convergence between M1a-contra and other M1a patients with primary tumors greater than or equal to 3 cm or mediastinal lymph node involvement. Proportional hazard modeling indicated that T1-2N0-1M1a-contra patients exhibit OS not significantly different (p = 0.258) from that predicted with comparable T and N stage disease plus a second early-stage primary.

      CONCLUSIONS: Contralateral tumors in NSCLC carry a more favorable prognosis than other M1a or M1b disease. Primary tumor size and N stage may help distinguish M1a-contra patients with hematogenous metastasis from those with a synchronous, second primary.

      View details for PubMedID 26317917
  • NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Front Immunol
    Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM
    2015; 6: 368
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      Natural killer (NK) cells play a major role in cancer immunotherapies that involve tumor-antigen targeting by monoclonal antibodies (mAbs). NK cells express a variety of activating and inhibitory receptors that serve to regulate the function and activity of the cells. In the context of targeting cells, NK cells can be "specifically activated" through certain Fc receptors that are expressed on their cell surface. NK cells can express FcγRIIIA and/or FcγRIIC, which can bind to the Fc portion of immunoglobulins, transmitting activating signals within NK cells. Once activated through Fc receptors by antibodies bound to target cells, NK cells are able to lyse target cells without priming, and secrete cytokines like interferon gamma to recruit adaptive immune cells. This antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells is utilized in the treatment of various cancers overexpressing unique antigens, such as neuroblastoma, breast cancer, B cell lymphoma, and others. NK cells also express a family of receptors called killer immunoglobulin-like receptors (KIRs), which regulate the function and response of NK cells toward target cells through their interaction with their cognate ligands that are expressed on tumor cells. Genetic polymorphisms in KIR and KIR-ligands, as well as FcγRs may influence NK cell responsiveness in conjunction with mAb immunotherapies. This review focuses on current therapeutic mAbs, different strategies to augment the anti-tumor efficacy of ADCC, and genotypic factors that may influence patient responses to antibody-dependent immunotherapies.

      View details for PubMedID 26284063
  • Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. Radiother Oncol
    Morris ZS, Weichert JP, Saker J, Armstrong EA, Besemer A, Bednarz B, Kimple RJ, Harari PM
    2015 Sep; 116 (3): 504-9
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      BACKGROUND AND PURPOSE: CLR1404 is a phospholipid ether that exhibits selective uptake and retention in malignant tissues. Radiolabeled CLR1404 enables tumor-specific positron-emission tomography (PET) imaging ((124)I) and targeted delivery of ionizing radiation ((131)I). Here we describe the first preclinical studies of this diapeutic molecule in head and neck cancer (HNC) models.

      MATERIAL AND METHODS: Tumor-selective distribution of (124)I-CLR1404 and therapeutic efficacy of (131)I-CLR1404 were tested in HNC cell lines and patient-derived xenograft tumor models. Monte Carlo dose calculations and (124)I-CLR1404 PET/CT imaging were used to examine (131)I-CLR1404 dosimetry in preclinical HNC tumor models.

      RESULTS: HNC tumor xenograft studies including patient-derived xenografts demonstrate tumor-selective uptake and retention of (124)I-CLR1404 resulting in a model of highly conformal dose distribution for (131)I-CLR1404. We observe dose-dependent response to (131)I-CLR1404 with respect to HNC tumor xenograft growth inhibition and this effect is maintained together with external beam radiation.

      CONCLUSIONS: We confirm the utility of CLR1404 for tumor imaging and treatment of HNC. This promising agent warrants further investigation in a developing phase I trial combining (131)I-CLR1404 with reduced-dose external beam radiation in patients with loco-regionally recurrent HNC.

      View details for PubMedID 26123834
  • A molecular mechanism for the origin of a key evolutionary innovation, the bird beak and palate, revealed by an integrative approach to major transitions in vertebrate history. Evolution
    Bhullar BA, Morris ZS, Sefton EM, Tok A, Tokita M, Namkoong B, Camacho J, Burnham DA, Abzhanov A
    2015 Jul; 69 (7): 1665-77
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      The avian beak is a key evolutionary innovation whose flexibility has permitted birds to diversify into a range of disparate ecological niches. We approached the problem of the mechanism behind this innovation using an approach bridging paleontology, comparative anatomy, and experimental developmental biology. First, we used fossil and extant data to show the beak is distinctive in consisting of fused premaxillae that are geometrically distinct from those of ancestral archosaurs. To elucidate underlying developmental mechanisms, we examined candidate gene expression domains in the embryonic face: the earlier frontonasal ectodermal zone (FEZ) and the later midfacial WNT-responsive region, in birds and several reptiles. This permitted the identification of an autapomorphic median gene expression region in Aves. To test the mechanism, we used inhibitors of both pathways to replicate in chicken the ancestral amniote expression. Altering the FEZ altered later WNT responsiveness to the ancestral pattern. Skeletal phenotypes from both types of experiments had premaxillae that clustered geometrically with ancestral fossil forms instead of beaked birds. The palatal region was also altered to a more ancestral phenotype. This is consistent with the fossil record and with the tight functional association of avian premaxillae and palate in forming a kinetic beak.

      View details for PubMedID 25964090
  • Delivery of definitive dose external beam radiation in close proximity to an implanted deep brain stimulator. Pract Radiat Oncol
    Borkenhagen JF, Morris ZS, Hoberg JR, Kozak KR, Shapiro LQ
    2014 Sep-Oct; 4 (5): 294-7
  • Interaction of radiation therapy with molecular targeted agents. J Clin Oncol
    Morris ZS, Harari PM
    2014 Sep 10; 32 (26): 2886-93
    • More

      The development of molecular targeted therapeutics in oncology builds on many years of scientific investigation into the cellular mechanics of malignant transformation and progression. The past two decades have brought an accelerating pace to the clinical investigation of new molecular targeted agents, particularly in the setting of metastatic disease. The integration of molecular targeted agents into phase III clinical trial design has lagged in the curative treatment setting, particularly in combination with established therapeutic modalities such as radiation. In this review, we discuss the interaction of radiation and molecular targeted therapeutics. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with molecular targeted agents that may go unrecognized with conventional screening and monotherapy clinical testing of novel agents. By using epidermal growth factor receptor (EGFR) as a primary example, we discuss recent clinical studies that illustrate the potential synergy of molecular targeted agents with radiation and highlight the clinical value of such interactions. For various molecular targeted agents, their greatest clinical impact may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach appear highly warranted.

      View details for PubMedID 25113770
  • Response. Chest
    Morris ZQ
    2014 Mar 01; 145 (3): 662-3
  • Thyroid-specific knockout of the tumor suppressor mitogen-inducible gene 6 activates epidermal growth factor receptor signaling pathways and suppresses nuclear factor-κB activity. Surgery
    Lin CI, Barletta JA, Nehs MA, Morris ZS, Donner DB, Whang EE, Jeong JW, Kimura S, Moore FD, Ruan DT
    2011 Dec; 150 (6): 1295-302
    • More

      BACKGROUND: Mitogen-inducible gene 6 (Mig-6) is a putative tumor suppressor gene and prognostic biomarker in papillary thyroid cancer. We hypothesized that Mig-6 knockout would activate pro-oncogenic signaling in mouse thyrocytes.

      METHODS: We performed a thyroid-specific knockout using the Cre/loxP recombinase system.

      RESULTS: Four knockout and 4 control mouse thyroids were harvested at 2 months of age. Immunoblotting confirmed Mig-6 ablation in knockout mice thyrocytes. Epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation levels were increased in Mig-6 knockout compared to wild-type mice. Total EGFR levels were similar in knockout and wild-type mice. However, EGFR was absent in the caveolae-containing membrane fraction of knockout mice, indicating that Mig-6 depletion is associated with a change in the membrane distribution of EGFR. Although p65 localized to the nucleus in wild-type mice, it was distributed in both cytoplasm and nucleus in knockouts, suggesting that Mig-6 loss decreases p65 activity.

      CONCLUSION: Our results confirm the feasibility of targeted, thyroid-specific gene knockout as a strategy for studying the relevance of specific genes in thyroid oncogenesis. We suggest that the loss of Mig-6 alters the membrane distribution of EGFR, which may limit receptor degradation and activate this oncogenic signaling pathway.

      View details for PubMedID 22136853
  • Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci U S A
    Morris ZS, McClatchey AI
    2009 Jun 16; 106 (24): 9767-72
    • More

      The epidermal growth factor receptor (EGFR) has frequently been implicated in hyperproliferative diseases of renal tubule epithelia. We have shown that the NF2 tumor suppressor Merlin inhibits EGFR internalization and signaling in a cell contact-dependent manner. Interestingly, despite the paucity of recurring mutations in human renal cell carcinoma (RCC), homozygous mutation of the NF2 gene is found in approximately 2% of RCC patient samples in the Sanger COSMIC database. To examine the roles of Merlin and EGFR in kidney tumorigenesis, we generated mice with a targeted deletion of Nf2 in the proximal convoluted epithelium using a Villin-Cre transgene. All of these mice developed intratubular neoplasia by 3 months, which progressed to invasive carcinoma by 6-10 months. Kidneys from these mice demonstrated marked hyperproliferation and a concomitant increase in label-retaining putative progenitor cells. Early lumen-filling lesions in this model exhibited hyperactivation of EGFR signaling, altered solubility of adherens junctions components, and loss of epithelial polarity. Renal cortical epithelial cells derived from either early or late lesions were dependent on EGF for in vitro proliferation and were arrested by pharmacologic inhibition of EGFR or re-expression of Nf2. These cells formed malignant tumors upon s.c. injection into immunocompromised mice before in vitro passage. Treatment of Vil-Cre;Nf2(lox/lox) mice with the EGFR inhibitor erlotinib halted the proliferation of tumor cells. These studies give added credence to the role of EGFR signaling and perhaps Nf2 deficiency in RCC and describe a rare and valuable mouse model for exploring the molecular basis of this disease.

      View details for PubMedID 19487675
  • The neurofibroma cell of origin: SKPs expand the playing field. Cell Stem Cell
    Morris ZS, McClatchey AI
    2009 May 08; 4 (5): 371-2
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      Mounting evidence suggests that stem/progenitor cells may be the cells of origin for many tumor types. In this issue of Cell Stem Cell, Le et al. (2009) demonstrate that skin-derived precursors (SKPs) can initiate dermal neurofibromas and highlight the importance of the microenvironment in the formation of this complex tumor.

      View details for PubMedID 19427284
  • Inter- and intraspecific variation in excited-state triplet energy transfer rates in reaction centers of photosynthetic bacteria. Photochem Photobiol
    Laible PD, Morris ZS, Thurnauer MC, Schiffer M, Hanson DK
    2003 Aug; 78 (2): 114-23
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      In protein-cofactor reaction center (RC) complexes of purple photosynthetic bacteria, the major role of the bound carotenoid (C) is to quench the triplet state formed on the primary electron donor (P) before its sensitization of the excited singlet state of molecular oxygen from its ground triplet state. This triplet energy is transferred from P to C via the bacteriochlorophyll monomer B(B). Using time-resolved electron paramagnetic resonance (TREPR), we have examined the temperature dependence of the rates of this triplet energy transfer reaction in the RC of three wild-type species of purple nonsulfur bacteria. Species-specific differences in the rate of transfer were observed. Wild-type Rhodobacter capsulatus RCs were less efficient at the triplet transfer reaction than Rhodobacter sphaeroides RCs, but were more efficient than Rhodospirillum rubrum RCs. In addition, RCs from three mutant strains of R. capsulatus carrying substitutions of amino acids near P and B(B) were examined. Two of the mutant RCs showed decreased triplet transfer rates compared with wild-type RCs, whereas one of the mutant RCs demonstrated a slight increase in triplet transfer rate at low temperatures. The results show that site-specific changes within the RC of R. capsulatus can mimic interspecies differences in the rates of triplet energy transfer. This application of TREPR was instrumental in defining critical energetic and coupling factors that dictate the efficiency of this photoprotective process.

      View details for PubMedID 12945578

Contact Information

Zachary Morris, MD, PhD

1111 Highland Avenue, 3131 WIMR,
Madison, WI 53705