Flavopiridol Reverses Platinum Resistance in Ovarian Cancer

卵巢癌是美国女性癌症死亡的第五大原因，导致70%的人死亡 每年有15,000多人死于这种疾病。虽然大多数女性最初对 含有铂的方案，通常会产生顺铂耐药。我们之前的研究已经 证明了非那匹利多，一种小分子的细胞周期蛋白依赖性激酶的抑制剂，与DNA相互作用。 并选择性地干扰与卵巢癌有关的转录因子STAT3介导的转录 发病机制。此外，我们还证明了非那匹利多可增强细胞内顺铂。 卵巢癌细胞的蓄积、铂-DNA加合物和顺铂的细胞毒性。这些数据导致了 Favopiridol+顺铂治疗铂耐药卵巢癌正在进行的II期试验显示 33%的有效率(11%的缓解率，22%的缓解率)和更高的总存活率(16个月与6个月) 接受历史第二阶段方案治疗的患者)。 为了推广这些有希望的成果，我们现在为孢子项目#4提出以下具体目标： 目的1：探讨非那匹利多联合顺铂治疗卵巢癌的协同和耐药机制。 我们将研究药物诱导的顺铂转运蛋白活性、STAT3信号或 多肽表达(例如，Mcl-1、BRCA1/2和HtrAI)，以获得对 将允许a)选择最有可能受益于黄烷醇+顺铂治疗的患者，以及 B)制定战略，克服对这种疗法的抗药性。 目的2：确定非那普利多+顺铂疗效的生物标志物。我们将研究 Favopiridol对已知多肽的预处理水平的预测价值 (例如，Mcl-1、磷酸化STAT3、p65NFDB)，并鉴定其他候选预测生物标志物 通过对参加我们正在进行的非那普利多+顺铂的患者的样本进行分析 11期试验。 目标3：利用临床前模型评估各种策略，以最大限度地提高 黄烷醇/顺铂联合治疗卵巢癌。使用鼠标模型，我们将 检查f/7三联用药的效果(例如，非那匹利多+顺铂联合 紫杉醇、卡培他滨或吉西他滨)，以确定我们可以推进到

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