Flavopiridol Reverses Platinum Resistance in Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer mortality in women in the U.S., killing 70% of afflicted patients and accounting for over 15,000 deaths annually. While most women initially respond to platin-containing regimens, cisplatin resistance commonly develops. Our previous studies have demonstrated that fiavopiridol, a small molecule inhibitor of cyclin-dependent kinases, interacts with DNA and selectively disrupts transcription mediated by STAT3, a transcription factor implicated in ovarian cancer pathogenesis. In addition, we have demonstrated that fiavopiridol enhances intracellular cisplatin accumulation, Pt-DNA adducts and cisplatin cytotoxicity in ovarian cancer cell lines. These data led to an ongoing phase II trial of fiavopiridol + cisplatin in platinum-resistant ovarian cancer demonstrating a 33% response rate (11% CRs, 22% PRs) and enhanced overall survival (16 mos vs. 6 mos for analogous patients treated with historical Phase II regimens). To extend these promising results, we now propose the following Specific Aims for SPORE Project #4: Aim 1: Define the mechanisms of fiavopiridol + cisplatin synergy and resistance in ovarian cancer. We will examine drug-induced alterations in cisplatin transporter activity, STAT3 signaling or polypeptide expression (e.g., Mcl-1, BRCA1/2, and HtrAI) in order to gain mechanistic insight that will allow a) selection of the patients most likely to benefit from ^flavopirldol + cisplatin therapy and b) formulation of strategies to overcome resistance to this regimen. Aim 2: Identification of biomarkers of response to fiavopiridol + cisplatin. We will examine the predictive value of pretreatment levels of polypeptides known to be affected by fiavopiridol (e.g., Mcl-1, phospho-STAT3, p65 NFDB) and identify additional candidate predictive biomarkers through analysis of samples obtained from patients enrolled in our ongoing fiavopiridol + cisplatin phase 11 trial. Aim 3: Utilize preclinical models to evaluate various strategies for maximizing the impact of the flavopiridol/cisplatin combination on ovarian cancer treatment. Using mouse models, we will examine the effects of f/7ree-agent combinations (e.g., fiavopiridol + cisplatin combined with paclltaxel, capecitabine, or gemcitabine) to identify a strategy that we can take forward into the