Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: A critical need for optimal management of human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) patients is the development of therapeutic strategies to exploit the inherent vulnerabilities of this unique disease. We identified fenofibrate, an FDA-approved drug, as a potent anti-cancer agent for HPV+ HNSCC. Fenofibrate induced the accumulation of the p53 tumor suppressor and re-programmed the tumor microenvironment to drive immune cell infiltration. We provide compelling evidence to reposition fenofibrate as a single agent or in combination with standard therapies for the HPV+ HNSCC setting. ABSTRACT: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.