Overcoming platinum resistance in ovarian cancer through BET inhibition.

通过 BET 抑制克服卵巢癌的铂耐药性。

• 批准号: 10478847
• 负责人: Rugang Zhang
• 金额: $ 27.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478847
• 关键词: 19p13; Biological Markers; Bromodomain; Carboplatin; Carcinoma; Cell Line; Cells; Characteristics; Chemoresistance; Clinical; Clinical Management; Companions; Diagnostic tests; Disease Resistance; Dose; Epigenetic Process; Epithelial ovarian cancer; Genes; Goals; Human; In Vitro; Intervention; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Methods; Mission; Patients; Phase I Clinical Trials; Platinum; Pre-Clinical Model; Prior Therapy; Prognosis; Proteins; Public Health; Recurrence; Relapse; Research; Resistance; Safety; Serous; Specimen; Testing; Therapeutic; Translations; United States National Institutes of Health; Up-Regulation; aldehyde dehydrogenases; arm; base; cancer cell; cancer therapy; chemotherapy; clinical application; clinical efficacy; clinical predictors; companion diagnostics; genomic locus; in vivo; inhibitor; innovation; knock-down; mortality; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; phase I trial; predicting response; predictive marker; response; small molecule; standard of care; stem; stem-like cell; therapeutic target; therapy outcome; translational study; treatment response; tumorigenesis

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.

项目3：项目摘要 该提案的总体目标是确定溴化妇女和末端（BET）蛋白是否是否 BRD4是延迟和/或克服基于铂基的卵巢的有希望的治疗靶标 癌症护理标准。化学抗性是卵巢癌死亡率高的主要原因 特别是在最常见的高级浆液性癌（HGSC）中。大量证据表明 具有癌症干细胞（CSC）特征的细胞有助于化学疗法抗性。假定 卵巢癌CSC通常以增加的醛脱氢酶（ALDH）活性为特征。这 是一项假设驱动的翻译研究，发现将是评估抑制剂是否关键的 结合铂是克服铂耐药性的有效方法 抑制卵巢癌CSC中的ALDH活性。我们将与Incyte，Inc。合作使用他们的赌注 抑制剂INCB57643在患者中被证明是安全的。因此，BET抑制剂很容易立即使用 卵巢癌的翻译。拟议的研究是基于我们最近的发现确定的抑制作用 BET抑制剂的BRD4活性足以消除ALDH阳性CSC。我们的中心假设是 可以通过消除ALDH阳性癌变干细胞来克服铂的耐药性 使用临床适用的小分子抑制剂INCB57643靶向BRD4。三个具体目标是 提议：AIM 1将探索BET抑制剂INCB57643和卡铂的组合 HGSOC在1期临床试验中； AIM 2将研究靶向组合治疗策略 BRD4在HGSC细胞系和患者衍生的异种移植物中使用BET抑制剂INCB57643和卡泊蛋白；和 AIM 3将确定与响应BET抑制剂INCB57643和 HGSOC中的卡铂组合。拟议的研究具有很高的创新性，因为它们挑战 当前的研究/临床范式，通过结合BET来促进表观遗传学疗法的新概念 抑制剂和铂金，并利用创新方法来探索新的干预策略 卵巢癌的化学疗法耐药性。拟议的研究具有很高的影响，因为这些研究 通过克服铂抗性，将制定具有持久治疗结果的治疗策略 通过消除癌症干细胞，这是卵巢癌临床管理的主要挑战。