Hedgehog signaling in head and neck cancer stem cells, and its role in resistance to EGFR inhibitors Abstract Epidermal growth factor receptor (EGFR) inhibitors are standard of care in head and neck squamous cell cancer (HNSCC) but the efficacy is low and resistance (primary or acquired) is almost universal. We have generated a unique direct patient tumor model (DPTM) of HNSCC that is optimal to study cancer stem cells (CSC). We have found putative CSC that are enriched in tumors after therapy and are able to generate tumors after sorting and implantation, and that have very intense signaling in the hedgehog pathway that is associated with CSC. Our overarching goal is to identify and characterize CSC and what vulnerabilities they may have. In this research proposal we plan to ascertain the role of CSC and their signaling through hedgehog in resistance to conventional therapies, particularly EGFR inhibitors. First we will identify bona fide CSC, and will knockdown the pathway by genetic means. Then, we will conduct advanced animal studies testing rational combinations of conventional therapy with pharmacological hedgehog inhibition. Finally we will test some of the above observations in samples from HNSCC patients undergoing conventional therapy as validation. The significance of these studies is that they will help us understand the basis of resistance to therapies that are in current use. This project tests both the relevance of hedgehog signaling in CSC and of the hedgehog pathway in HNSCC. If positive, these data will provide the rationale to explore hedgehog inhibitors in HNSCC in clinical trials, adding a new potential avenue for these patients. Both are relevant unmet needs.
The overarching goal of this project is to characterize the precursor or cancer stem cells that are responsible for treatment failures in head and neck cancer, and identify their susceptibility. We will use a model of head and neck cancer that is derived directly from patient's tumors. Although more cumbersome to work with than other simpler models, these tumors more faithfully represent the different components of a cancer, and thus are more informative. We have found that a particular pathway is involved in allowing those reserve cells to survive treatment, and since we have inhibitors available we plan to test their efficacy alone, and with regular chemotherapy. Because our group is also testing the same drugs in patients, if we make any relevant discovery we will be in a very good position to initiate testing in head and neck cancer patients. We will also seek ways to determine what patients will benefit from these drugs, to individualize caner therapy.
|Morton, J J; Bird, G; Keysar, S B et al. (2016) XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene 35:290-300|
|Morton, J Jason; Bird, Gregory; Refaeli, Yosef et al. (2016) Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap. Cancer Res 76:6153-6158|
|Gan, Gregory N; Altunbas, Cem; Morton, John J et al. (2016) Radiation dose uncertainty and correction for a mouse orthotopic and xenograft irradiation model. Int J Radiat Biol 92:50-6|
|Le, Phuong N; McDermott, Jessica D; Jimeno, Antonio (2015) Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther 146:1-11|
|Gan, Gregory N; Eagles, Justin; Keysar, Stephen B et al. (2014) Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers. Cancer Res 74:7024-36|
|Keysar, Stephen B; Le, Phuong N; Anderson, Ryan T et al. (2013) Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer. Cancer Res 73:3381-92|
|Jimeno, Antonio; Weiss, Glen J; Miller Jr, Wilson H et al. (2013) Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res 19:2766-74|
|Keysar, Stephen B; Astling, David P; Anderson, Ryan T et al. (2013) A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol 7:776-90|
|Anderson, Ryan T; Keysar, Stephen B; Bowles, Daniel W et al. (2013) The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas. Mol Cancer Ther 12:1994-2005|
|White, Ruth A; Neiman, Jill M; Reddi, Anand et al. (2013) Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. J Clin Invest 123:4390-404|
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