Small molecule therapeutics for HPV associated cancers

Approximately 5% of cancers are caused the by high-risk human papillomaviruses. Although effective preventive vaccines will reduce this cancer burden significantly over the next several decades, they have no therapeutic effect for those already infected, and who therefore remain at risk for HPV driven cancers. HPV-associated cancers are dependent upon the continued expression of viral E6 and E7 oncogenes. The oncogenic function of E6 relies on its ability to induce p53 ubiquitin-dependent degradation. Since p53 is generally wildtype in HPV-associated cancers, p53 stabilization arrests proliferation, induces apoptosis and/or results in senescence. Using a live cell, image-based high-throughput platform to identify compounds that stabilize p53 and/or affect viability in HPV-positive cancer HeLa cells, we have recently completed a screen of the 50,000 compound ChemBridge 2020 library at the ICCB-Longwood. We have identified a number of hits and have now validated that a subset of these hits stabilize endogenous p53 in non-reporter Hela cells. Our goals now are to complete the validation of these top hits, determine whether or not they have HPV-specificity, identify their cellular targets, and optimize their activities through near neighbor analysis with a focus on the identification of lead therapeutic compounds for HPV-associated cancers. The main focus is on HPV-positive cancers such as cervical cancer and head and neck oropharyngeal cancers. It is possible that HPV-specific compounds could also subsequently be evaluated and developed for treatment of high grade HPV-positive precancers.