Cancer Initiating Cells and Treatment Resistance

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 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with an annual incidence of approximately 600,000 cases worldwide (1). Over the last several decades, diagnosis and management of HNSCC have advanced; however, the 5-year survival rate has remained static at around 50%. Treatment resistance, local-regional recurrence and distant metastasis are the major causes of morbidity and mortality in HNSCC patients. Cancer initiating cells (CICs) or cancer stem cells are a small sub-set of cancer cells within the tumor with the exclusive capacity to divide and expand the CIC pool or to differentiate into heterogeneous non-tumorigenic cells that constitute the bulk of the tumor. There is emerging evidence that CICs are refractory to chemotherapy and radiation and responsible for disease recurrence and progression. Therefore, elimination of CICs will have a dramatic positive impact on the survival of HNSCC patients. Human papillomavirus (HPV) is recognized as a risk factor for the development of HNSCC in particular oropharyngeal SCC. HPV16 is the most prevalent subtype and accounts for ~90% of HPV-positive HNSCC. Patients with HPV16-positive HNSCC tend to present to the clinic with more advanced disease due to increased nodal involvement than patients with HPV-negative HNSCC. Paradoxically, there is considerable evidence that HPV16-positive HNSCC has superior outcome compared to HPV-negative HNSCC treated with platinum- based regimens. While working on CIC biology in HNSCC, we accumulated intriguing experimental evidence to explain these seemingly paradoxical clinical observations. We found a striking difference in the number and phenotype between HPV16-positive and HPV-negative HNSCC CICs. HPV16-positive HNSCC has a higher intrinsic CIC pool than HPV-negative HNSCC. Surprisingly, HPV16-positive CICs are dramatically more responsive to cis-platinum treatment then HPV-negative CICs. This finding contradicts the "CIC hypothesis" postulate that CICs are universally resistant to conventional therapies and provide intriguing evidence that CICs are heterogeneous in response to a standard chemotherapeutic, cis-platinum. In this application, we will leverage our preliminary data to study clinically relevant questions regarding CIC biology in HNSCC. How does HPV16 modulate CICs to respond to cis-platinum and/or radiation? What is the role of p300 in modulating treatment response in HNSCC CICs? And how do we reprogram HPV-negative HNSCC CICs to respond to conventional treatment modalities? At the conclusion of this proposed work, we will provide novel insights into CIC biology that may lead to the advancement of innovative therapeutics to ablate the treatment-resistant HPV-negative HNSCC CIC population.