PDZ-targeted Therapeutics for Cervical Cancer

DESCRIPTION (provided by applicant): Oncogenic variants of human papilloma virus (HPV) have been correlated with cervical cancer at a frequency of gt 99%, and also cause penile, anal and head and neck cancers. We have recently determined that all oncogenic E6 proteins bind to the first PDZ domain of MAGI1 protein, an interaction that is critical for both HPV-induced carcinogenesis and for maintenance of the cancerous state in HPV-positive cells. We have identified a novel lead small molecule inhibitor (AVC-7) of the interaction between E6 oncoprotein and MAGI1- PDZ1. Interruption of the E6 / MAGI1-PDZ1 interaction results in down regulation of E6 and E7 oncoproteins, restoration of the tumor suppressor p53, and induction of apoptosis in cervical cancer cell lines. In this grant, Arbor Vita proposes to identify more potent derivatives of AVC-7 and to demonstrate the efficacy of these derivatives in treatment of cervical cancer in vitro and in vivo. Specifically, Arbor Vita proposes to (1) Design derivatives of AVC-7 with increased potency in binding to MAGI1 and improved water solubility, (2) Demonstrate the selective biological activity of AVC-7 derivatives in cultured HPV-positive cervical cancer cells, and (3) Demonstrate efficacy of the most promising compound in a murine xenograft tumor model. Successful completion of the grant will result in a 10 mM (or better) inhibitor of the E6 / MAGI1-PDZ1 interaction that selectively induces apoptosis in HPV-positive cancer cells and significantly decreases tumor growth in the murine xenograft model. This proposal will be followed by a Phase 2 application to advance a lead compound towards human clinical testing via PK/PD studies, GLP toxicology studies, and GMP drug manufacturing and formulation. PUBLIC HEALTH RELEVANCE: HPV-related cancers such as cervical, anal, penile, and head and neck are serious disorders that affect hundreds of thousands of people and for which there are no approved drugs directed at the underlying cause. Arbor Vita has characterized a novel target of the oncogenic HPV E6 proteins named MAGI1, and has identified early lead drugs that can reduce levels of cancer causing E6 oncoproteins while restoring levels of the p53 tumor suppressor. p53 is a key protein that protects cells from becoming cancerous.