Small Molecule Inhibitors Against HPV-Induced Orophageal Cancers

PROJECT SUMMARY/ABSTRACT Human Papillomavirus (HPV) is the major cause of head and neck squamous cell carcinomas; most oropharyngeal (75%) and other head and neck cancers are caused by chronic HPV infection. Metastatic HPV- associated cancers are minimally responsive to current treatments and uniformly fatal. The most recent American Cancer Society annual statistics for oral/oropharyngeal cancers in the U.S. indicate 54,540 new diagnoses and 11,540 deaths. Novel therapies are therefore sorely needed. HPV-associated cancer cells require direct dysregulation of cells through viral E6 and E7 oncoproteins, which are indispensable for tumorigenesis. These proteins are essential for ongoing tumor cell survival, and therefore serve as ideal therapeutic targets. Knockdown of E6 or E7 using siRNA in HPV-transformed cells results in apoptosis. This pilot R21 project describes plans to screen for druggable small molecule antagonists of HPV E6 or E7 oncoproteins. The overall strategy will be to screen small molecule libraries for compounds that cause specific death of tongue cancer squamous cell lines with HPV, but not those without HPV: o Aim 1: To create tongue carcinoma cell clones differing in HPV status and fluorescence color. o Aim 2: To screen small molecule libraries for drug candidates causing HPV-specific cell death. o Aim 3: To test the function of drug candidates to induce death of other HPV-transformed cells. Successful completion of this project would identify drug candidates that induce apoptosis of HPV-transformed oral cancer cells through interference with E6 or E7.