Flavopiridol Reverses Platinum Resistance in Ovarian Cancer

卵巢癌是美国女性癌症死亡率的第五大原因，杀死70%的 每年有超过15，000人因此而死亡。虽然大多数女性最初对 在含铂方案中，通常会产生顺铂耐药性。我们以往的研究 证明了非阿伏吡啶醇，一种细胞周期蛋白依赖性激酶的小分子抑制剂， 并选择性地破坏STAT 3介导的转录，STAT 3是一种与卵巢癌有关的转录因子 发病机制此外，我们已经证明，fiavopiridol增强细胞内顺铂 在卵巢癌细胞系中的蓄积、Pt-DNA加合物和顺铂细胞毒性。这些数据导致了 正在进行的非阿伏吡啶醇+顺铂治疗铂类耐药卵巢癌的II期试验显示， 33%的缓解率（11% CR，22% PR）和提高的总生存期（16个月对比类似物的6个月） 接受历史II期方案治疗的患者）。 为了扩展这些有希望的结果，我们现在为SPORE项目#4提出以下具体目标： 目的1：探讨非沃吡啶醇联合顺铂治疗卵巢癌的增效和耐药机制。 我们将研究药物诱导的顺铂转运蛋白活性、STAT 3信号传导或 多肽表达（例如，Mcl-1、BRCA 1/2和HtrAI），以便获得 将允许a）选择最有可能受益于黄酮吡醇+顺铂疗法的患者，以及 B）制定策略以克服对该方案的抗性。 目的2：鉴定对氟阿吡啶醇+顺铂反应的生物标志物。我们会研究 已知受非阿伏吡啶醇影响的多肽的预处理水平的预测值 (e.g., Mcl-1、磷酸化STAT 3、p65 NFDB）并识别其他候选预测生物标志物 通过分析从参加我们正在进行的fiavopiridol +顺铂的患者中获得的样本 第11期试验 目标3：利用临床前模型来评估各种策略，以最大限度地发挥 flavopiridol/cisplatin联合治疗卵巢癌使用小鼠模型，我们将 检查F/7 REE-试剂组合的效果（例如，非沃吡啶醇+顺铂联合 紫杉醇，卡培他滨或吉西他滨），以确定我们可以采取的策略 “下一代”含flavopiridol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、动物模型和 马约卵巢孢子的生物统计学核心，旨在加强对 flavopirldol单独和联合治疗卵巢癌，从而推进临床开发 作为一种潜在的有前途的卵巢癌治疗剂的非阿伏吡啶醇。 相关性（参见说明）： 该团队已经进行了一项II期临床试验，显示了一种新的令人鼓舞的初步结果。 药物组合，fiavopiridol和顺铂。这个项目将研究药物组合是如何起作用的， 寻找肿瘤标本中的生物标志物，这些生物标志物可能预测谁将从这种方案中受益，并测试三个- 实验室中的药物组合，以确定那些可以改善卵巢癌治疗的药物。

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.