Flavopiridol Reverses Platinum Resistance in Ovarian Cancer

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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 "next generation" flavopiridol-containing ovarian cancer clinical trial. These studies, which make extensive use of the Biospecimens and Patient Registry, Animal Models and Biostatistics Cores of the Mayo Ovarian SPORE, are designed to bolster knowledge of the effects of flavopirldol both alone and In combination in ovarian cancer, thereby advancing clinical development of fiavopiridol as a potentially promising ovarian cancer therapeutic. RELEVANCE (See instructions): This team has perfomned a phase II clinical trial that shows highly encouraging preliminary results for a new drug combination, fiavopiridol and cisplatin. This project will investigate how the drug combination works, look for biomarkers in tumor specimens that might predict who will benefit from this regimen, and test three- drug combinations in the lab to identify those that could improve ovarian cancer treatment.