Overcoming platinum resistance in ovarian cancer through BET inhibition.

项目3：项目总结 这项提案的总体目标是确定溴多曼和末端外(BET)蛋白 BRD4是延缓和/或克服铂类卵巢耐药的有前途的治疗靶点 癌症护理的标准。化疗耐药性是卵巢癌和卵巢癌高死亡率的主要原因。 尤其是最常见的高级别浆液性癌(HGSC)。确凿的证据表明 具有肿瘤干细胞(CSC)特征的细胞会导致化疗耐药。推定 卵巢癌干细胞的典型特征是乙醛脱氢酶(ALDH)活性升高。这 是一项假设驱动的翻译研究，这一发现将对评估BET抑制剂是否 与铂结合是克服铂耐药性的有效方法，通过 抑制卵巢癌CSCs中ALDH活性。我们将与Incell，Inc.合作，使用他们的BET 在患者中被证明是安全的抑制剂INCB57643。因此，BET抑制剂很容易就可以立即获得 翻译成卵巢癌。拟议的研究是基于我们最近的发现确定的抑制 BET抑制剂对BRD4活性的抑制足以根除ALDH阳性的CSCs。我们的中心假设是 通过消除ALDH阳性的癌症干细胞，可以克服对铂的耐药性 使用临床适用的小分子BET抑制剂INCB57643靶向BRD4。三个具体目标是 建议：目的1将探讨BET抑制剂INCB57643与卡铂联合治疗慢性粒细胞白血病 HGSOC正在进行一期临床试验；Aim 2将研究靶向联合治疗策略 在HGSC细胞系和患者来源的异种移植中使用BET抑制剂INCB57643和卡铂的BRD4；以及 AIM 3将确定与BET抑制剂INCB57643和INCB57643的反应相关的伴随生物标志物 HGSOC中的卡铂联合应用。拟议的研究具有很高的创新性，因为它们挑战 目前的研究/临床范例，通过结合BET，为表观遗传学治疗提供了新的概念 抑制剂和铂，并利用创新方法探索新的干预策略 卵巢癌患者的化疗耐药。拟议的研究具有很高的影响力，因为这些研究 将通过克服铂耐药来开发具有持久治疗结果的治疗策略 通过根除癌症干细胞，是卵巢癌临床治疗中的一大挑战。

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.