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 “下一代”含黄烷醇的卵巢癌临床试验。 这些研究广泛使用了生物标本和患者登记处、动物模型和 梅奥卵巢孢子的生物统计核心，旨在支持对 单药和联合治疗卵巢癌，从而促进卵巢癌的临床发展 非洛必利作为一种有潜力的卵巢癌治疗药物。 相关性(请参阅说明)： 该团队已经完成了二期临床试验，显示出非常令人鼓舞的新的 药物组合，非那匹利多和顺铂。这个项目将调查药物组合是如何发挥作用的， 在肿瘤标本中寻找可能预测谁将从这种方案中受益的生物标记物，并测试三种- 实验室中的药物组合，以确定哪些可以改善卵巢癌的治疗。

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.