I am currently a third-year graduate student in the Cellular and Molecular Pathology (CMP) program at UW–Madison. My long-term research interests include identification of novel molecular therapeutics for use in cancer therapies. I strongly desire to devote my skills and knowledge to understanding the dynamic systems of the body at a molecular and biochemical level in order to personalize treatments for cancer patients. Under the guidance of Dr. Deric Wheeler, I have entered into the field of cancer biology and investigating receptor tyrosine kinases (RTKs) that contribute to therapeutic resistance in cancer. My thesis project focuses on studying AXL, an RTK that leads to drug resistance in head and neck squamous cell carcinoma (HNSCC) and triple negative breast cancer (TNBC). I am investigating AXL’s signaling role in these cancers and the benefit of targeting AXL as a cancer therapy for patients. Ultimately, my dream would be to see my research on AXL translate directly into a clinical trial for patients suffering from these diseases.
BS, University of Northwestern–St. Paul, Biochemistry, Biology (2015)
Selected Honors and Awards
MTCT AACR Scholar-in-Training Award (2017)
Cellular and Molecular Pathology T32 Fellowship (2016–2017)
Graduate Summa Cum Laude (2015)
Member of the Eagle Scholar Honors Program, University of the Northwestern–St. Paul (2012–2015)
Tri-Beta Biological Honors Society-Omicron Sigma Chapter (2012–2015)
Dean's List, University of the Northwestern–St. Paul (2011–2015)
Boards, Advisory Committees and Professional Organizations
CMP Student Seminar Facilitator
CMP Student Recruitment Leader
Member of the American Association for the Advancement of Science (AAAS)
Member of AACR–Women in Cancer Research
Head and Neck Cancer, Triple Negative Breast Cancer
AXL mediates cetuximab and radiation resistance through tyrosine 821 and the c-ABL kinase pathway in head and neck cancer. Clin Cancer Res
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 May 21; :
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 radiation therapy 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 anti-tumor response.View details for PubMedID 32439698
MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther
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 11; 17 (11): 2297-2308
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.View details for PubMedID 30093568
Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol. Mol Cancer Ther
Pearson HE, Iida M, Orbuch RA, McDaniel NK, Nickel KP, Kimple RJ, Arbiser JL, Wheeler DL
2018 01; 17 (1): 204-214
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.View details for PubMedID 29054984