Exploiting differences in HPV oncoprotein function among oropharyngeal cancers to personalize therapy - PROJECT SUMMARY Toxicities of treating human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) with radiation plus cisplatin create lifelong disabilities in survivors of this increasingly common cancer. Reducing radiation doses and cisplatin use for HPV+ OPSCC is impeded by difficulty distinguishing a subset of cases with high recurrence risk, and the mechanisms of therapy resistance in such patients are unclear. These knowledge gaps contribute to both overtreating easily curable patients and ineffective therapy for high-risk cases. Opportunity to overcome these barriers arose from our finding that the HPV+ OPSCCs predisposed to recurrence upregulate a master driver of mitochondrial biogenesis, the PGC-1/ERR gene regulatory axis. These tumors have potential to exploit the antioxidant systems fueled by mitochondria to neutralize oxidative stress induced by hypoxia, nutrient depletion, metastatic spread, and current therapies. HPV+ OPSCCs with high mitochondrial mass expressed less HPV E6 oncoprotein and more p53, its canonical target for degradation. Because increasing E6 repressed mitochondrial biogenesis and sensitized to cisplatin and radiation, certain tumors may find selective advantage in partly downregulating E6 while upregulating other oncogenic drivers. Interventions to target such drivers and phenocopy the subset of E6’s activities that induce oxidative stress offer new avenues for overcoming therapy resistance. Thus, our overall hypothesis is that p53- induced activation of the PGC-1/ERR axis in presence of reduced E6 expression leads to poor survival for certain HPV+ OPSCCs but also creates targetable vulnerabilities in them. Aim 1 will elucidate the interactions among HPV E6 levels, mitochondrial mass and function, and HPV+ OPSCC progression. For this purpose, we will dissect the contribution of E6 levels to the range of mitochondrial mass and antioxidant capacity seen across different tumors and malignant cells in individual tumors. Altering mitochondrial mass by varying E6 levels will be tested for impact on growth, invasion, and metastasis. E6’s effects on mitochondrial function and tumor progression will then be assessed for dependence on p53 and PGC-1α individually and combination, and p53’s role in regulating PGC-1 expression and function will be determined in this context. Aim 2 will define strategies to sensitize HPV+ OPSCCs with high mitochondrial mass. Effects of E6 and mitochondrial mass on responses to radiation and cisplatin individually and in combination will be characterized in detail. The chromatin regulatory enzymes Set7 and PRMT1, which enhance PGC-1 function and are inhibited by E6, will then be tested for mechanistic roles in treatment resistance and for therapeutic utility in low-E6 tumors. Similarly, ERR‘s mechanistic role in this context will be defined, and its utility as a target for sensitizing to therapy will be tested. Testing our working model via these aims will enable prospective identification of therapy-resistant cases and define molecular targets to treat them. This effort will also allow creation of precise biomarkers and less toxic agents for treatment-sensitive cases, where current therapies leave lasting disability.
