Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling

使用高通量动态 BH3 分析确定卵巢肿瘤的联合疗法

• 批准号: 10307520
• 负责人: Kelley McQueeney
• 金额: $ 6.98万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307520
• 关键词: Affect; Animal Experiments; Animal Model; Apoptosis; Apoptotic; Ascites; Biological; Biological Assay; Cancer Etiology; Cancer Model; Cancer Patient; Carboplatin; Cell Death Signaling Process; Cells; Cessation of life; Chemicals; Classification; Clinical; Combined Modality Therapy; Data; Dependence; Diagnosis; Disease; Doxorubicin; Drug Combinations; Educational workshop; Ensure; Environment; Excision; Exposure to; Feedback; Foundations; Genetic; Goals; Grant; Graph; Hour; Immunoprecipitation; Laboratories; Lead; Libraries; Liquid substance; Maintenance Therapy; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mass Spectrum Analysis; Measures; Mediating; Mitochondria; Modeling; Molecular; Molecular Target; Organoids; Outcome; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Platinum; Population; Primary Neoplasm; Probability; Proteins; Recurrent disease; Regimen; Research; Research Personnel; Research Training; Resistance; Sampling; Solid Neoplasm; Techniques; Technology; Testing; Tumor Cell Line; Tumor-Derived; United States; Validation; Woman; Work; Xenograft Model; base; cancer cell; cancer therapy; career; cell killing; chemotherapy; combinatorial; cytotoxic; dimer; drug candidate; high throughput screening; improved; in vivo; inhibitor; innovation; meetings; mimetics; neoplastic cell; novel; novel strategies; ovarian neoplasm; patient derived xenograft model; patient population; patient response; precision medicine; pro-apoptotic protein; relapse patients; response; simulation; small molecule libraries; standard of care; statistics; success; symposium; targeted agent; treatment response; tumor; tumor heterogeneity; tumor xenograft

Project Summary/Abstract Ovarian cancer is the fifth leading cause of cancer deaths overall in women. The most recent estimates indicate that over 20,000 new cases will be diagnosed this year and nearly 14,000 women will die of the disease in the US in 2019 alone. The platinum-based standard of care cytotoxic regimen has remained largely stagnant for the last 15 years and recurrent disease is frequently platinum-resistant. Despite some recent success using molecular targeted agents and maintenance therapies (such as PARP inhibitors), the genetic complexity and lack of common molecular drivers make predicting patient responses difficult. Additionally, in relapsed patients, molecular changes induced by cancer therapies are multifaceted. Combining multiple drugs to treat ovarian cancer may be the most direct path to overcoming this intra-tumoral heterogeneity and acquired resistance to achieve more durable clinical responses. In an effort to capitalize on drugs that are approved and show patient benefit, this proposal seeks to identify compounds that can sensitize cells to apoptosis when combined with one of three drugs that act as cornerstones in ovarian cancer therapy: carboplatin, the PARP inhibitor olaparib, and doxorubicin. In the first aim a novel high-throughput screening platform called high-throughput dynamic BH3 profiling, will be used to identify whether a 24-hour ex vivo chemical treatment sensitizes tumor cells to mitochondrial mediated apoptosis. This will be performed using three ovarian cancer models: (1) freshly isolated tumor cells from primary patient ascites fluid, (2) organoid cultures derived from primary tumors, and (3) ovarian tumor cell lines. Preliminary data indicates that BH3 mimetics in combination with the standard of care drugs can increase apoptotic induction. In the second aim, the mechanism of drug-induced BH3 mimetic sensitivity will be investigated on the cellular, mitochondrial, and molecular level to determine which cellular contexts are likely to benefit from specific BH3 mimetic combinations. In the third and final aim compounds identified that increase apoptotic induction in combination with each of the three standard of care drugs will be tested in recently developed patient-derived luciferized tumor xenograft models of ovarian cancer. This will provide in vivo validation of the ability of specific drug combinations to cause tumor regression. This innovative approach offers both the potential to identify effective combinations to use in the platinum-sensitive, PARP-sensitive, and platinum-resistant settings, and the opportunity to determine molecular features that can identify populations that would benefit from these combinations. Supplementing the research component of the proposal with select courses and workshops, engagement in research meetings and seminars, and participation in scientific conferences will ensure an understanding of current concepts and techniques, constant feedback regarding the project's results and progress, and enhanced exposure to more translational work. Collectively, the research and training plan will provide a strong foundation upon which to build a career as a productive, independent cancer researcher.

项目概要/摘要 卵巢癌是女性癌症死亡的第五大原因。最新估计 表明今年将诊断出超过20,000例新病例，近14,000名妇女将死于该病 仅 2019 年就在美国发生了这种疾病。以铂为基础的细胞毒性治疗方案的标准在很大程度上仍然存在 过去 15 年停滞不前，复发性疾病通常对铂类耐药。尽管最近有一些 使用分子靶向药物和维持疗法（如 PARP 抑制剂）取得成功，遗传因素 复杂性和缺乏共同的分子驱动因素使得预测患者的反应变得困难。另外，在 对于复发患者来说，癌症治疗引起的分子变化是多方面的。多种药物联合使用 治疗卵巢癌可能是克服这种肿瘤内异质性的最直接途径 获得耐药性以实现更持久的临床反应。为了努力利用药物 该提案已获得批准并显示出对患者的益处，旨在识别可以使细胞敏感的化合物 与作为卵巢癌治疗基石的三种药物之一联合使用时会发生细胞凋亡： 卡铂、PARP 抑制剂奥拉帕尼和阿霉素。第一个目标是新颖的高通量筛选 平台称为高通量动态BH3分析，将用于鉴定是否24小时离体 化学治疗使肿瘤细胞对线粒体介导的细胞凋亡敏感。这将使用以下方法执行 三种卵巢癌模型：（1）从原发性患者腹水中新鲜分离的肿瘤细胞，（2）类器官 来自原发性肿瘤的培养物，和(3)卵巢肿瘤细胞系。初步数据表明，BH3 模拟物与标准治疗药物组合可以增加细胞凋亡诱导。在第二个目标中， 药物诱导的 BH3 模拟敏感性的机制将在细胞、线粒体和 分子水平以确定哪些细胞环境可能受益于特定的 BH3 模拟物 组合。在第三个也是最后一个目标中，确定了组合增加细胞凋亡诱导的化合物 三种护理标准药物中的每一种都将在最近开发的源自患者的荧光素化药物中进行测试 卵巢癌的肿瘤异种移植模型。这将为特定药物的能力提供体内验证 组合导致肿瘤消退。这种创新方法提供了识别有效的方法的潜力 用于铂敏感、PARP 敏感和铂抗性设置的组合，以及 确定分子特征的机会，这些特征可以识别将从这些中受益的人群 组合。通过选定的课程和研讨会补充提案的研究部分， 参加研究会议和研讨会以及参加科学会议将确保 了解当前的概念和技术，对项目结果的持续反馈以及 进步，并增加接触更多翻译工作的机会。总的来说，研究和培训计划将 为成为一名高效、独立的癌症研究人员奠定坚实的基础。