Overcoming platinum resistance in ovarian cancer through BET inhibition.

项目3：项目概要 该提案的总体目标是确定溴多曼和额外末端（BET）蛋白是否 BRD 4是一个有前途的治疗靶点，用于延迟和/或克服对铂类卵巢癌的耐药性。 癌症护理标准。化疗耐药性是卵巢癌高死亡率的主要原因， 特别是在最常见的高级别浆液性癌（HGSC）中。大量证据表明， 具有癌症干细胞样细胞（CSC）特征的细胞有助于化疗抗性。推定 卵巢癌CSC的典型特征是醛脱氢酶（ALDH）活性增加。这 是一项假设驱动的转化研究，这些发现对于评估BET抑制剂是否 与铂结合代表了克服铂抗性的有效方法， 抑制卵巢癌CSC中的ALDH活性。我们将与Incyte，Inc.合作。利用他们的赌注 INCB 57643在患者中被证明是安全的。因此，BET抑制剂可容易地用于直接施用。 在卵巢癌中的作用拟议的研究是基于我们最近的发现， BET抑制剂对BRD 4活性的抑制足以根除ALDH阳性CSC。我们的核心假设是 铂耐药性可以通过消除ALDH阳性癌症干细胞样细胞来克服， 使用临床适用的小分子BET抑制剂INCB 57643靶向BRD 4。三个具体目标是 提出：目的1将探索BET抑制剂INCB 57643和卡铂联合治疗 1期临床试验中的HGSOC;目标2将研究靶向的联合治疗策略 在HGSC细胞系和患者来源的异种移植物中使用BET抑制剂INCB 57643和卡铂的BRD 4;和 目的3将鉴定与BET抑制剂INCB 57643的应答相关的伴随生物标志物， 卡铂联合治疗HGSOC。这些研究具有高度创新性，因为它们挑战了 目前的研究/临床范例，有助于表观遗传治疗的新概念，结合BET 抑制剂和铂，并利用创新的方法，探索新的干预策略， 卵巢癌的化疗耐药性。拟议的研究具有很高的影响力，因为这些研究 将通过克服铂耐药性，开发具有持久治疗效果的治疗策略 通过根除癌症干细胞样细胞，这是卵巢癌临床管理的主要挑战。

PROJECT 3: PROJECT SUMMARY The overall goal of this proposal is to determine whether the bromodoman and extra-terminal (BET) protein BRD4 is a promising therapeutic target for delaying and/or overcoming resistance to platinum-based ovarian cancer standard of care. Chemoresistance is a major cause of the high mortality of ovarian cancer and in particular in the most common high-grade serous carcinoma (HGSC). Substantial evidence suggests that cells with cancer stem-like cells (CSC) characteristics contribute to chemotherapy resistance. Putative ovarian cancer CSCs are typically characterized by increased aldehyde dehydrogenase (ALDH) activity. This is a hypothesis-driven translational study, and the findings will be pivotal for evaluating whether BET inhibitors in combination with platinum represents an effective approach for overcoming platinum resistance by suppressing ALDH activity in ovarian cancer CSCs. We will collaborate with Incyte, Inc. to use their BET inhibitor INCB57643 that is proven safe in patients. Thus, the BET inhibitor is readily available for immediate translation in ovarian cancer. The proposed studies are based on our recent findings established that inhibition of BRD4 activity by BET inhibitors is sufficient to eradicate ALDH positive CSCs. Our central hypothesis is that platinum resistance can be overcome through eliminating ALDH positive cancer stem-like cells by targeting BRD4 using clinical applicable small molecule BET inhibitor INCB57643. Three Specific Aims are proposed: Aim 1 will explore the combination of BET inhibitor INCB57643 and carboplatin in patients with HGSOC in a Phase 1 clinical trial; Aim 2 will investigate the combinational therapeutic strategy of targeting BRD4 using BET inhibitor INCB57643 and carboplatin in HGSC cell lines and patient-derived xenografts; and Aim 3 will identify companion biomarkers that correlate with response to BET inhibitor INCB57643 and carboplatin combination in HGSOCs. The proposed studies are highly innovative because they challenge current research/clinical paradigms, contribute to new concepts for epigenetic therapeutics by combining BET inhibitors and platinum, and utilize innovative methods to explore new intervention strategies for chemotherapy resistance in ovarian cancer. The proposed studies are of high impact because these studies will develop therapeutic strategies with a durable therapeutic outcome by overcoming platinum resistance through eradicating cancer stem-like cells, a major challenge in the clinical management of ovarian cancer.