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.

项目摘要/摘要 卵巢癌是女性癌症死亡的第五大原因。最新的估计 预计今年将诊断出2万多例新病例，近14,000名妇女将死于 仅在美国就有2019年的疾病。以铂为基础的标准护理细胞毒性方案在很大程度上仍然存在 在过去的15年里一直停滞不前，而且复发的疾病往往对铂类药物具有抗药性。尽管最近有一些 成功地使用了分子靶向药物和维持疗法(如PARP抑制剂)，基因 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。此外，在 对于复发患者，癌症治疗引起的分子变化是多方面的。多种药物联合应用 治疗卵巢癌可能是克服这种肿瘤内异质性的最直接途径 获得性耐药性，以实现更持久的临床反应。为了努力利用那些 这项提议获得批准并显示出对患者的好处，旨在确定能够使细胞对 与卵巢癌治疗中起基石作用的三种药物之一联合使用时，细胞凋亡： 卡铂、PARP抑制剂奥拉帕利和阿霉素。在第一个目标中，一种新的高通量筛选 该平台名为高通量动态BH3图谱，将用于鉴定是否24小时体外 化学治疗使肿瘤细胞对线粒体介导的细胞凋亡敏感。这将使用以下工具执行 三种卵巢癌模型：(1)从原发患者腹水中新分离的肿瘤细胞；(2)有机物 来源于原发肿瘤的培养；(3)卵巢肿瘤细胞系。初步数据显示，BH3 模拟药物与标准护理药物相结合可以增加对细胞凋亡的诱导。在第二个目标中， 药物诱导的BH3模拟敏感性的机制将从细胞、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，化合物被确定为联合增加细胞凋亡的诱导。 与三种标准的护理药物中的每一种都将在最近开发的患者衍生的荧光素中进行测试 卵巢癌异种移植瘤模型的建立。这将为特定药物的体内能力提供验证 联合用药会导致肿瘤消退。这种创新的方法既提供了确定有效的 用于铂敏感、PARP敏感和抗铂设置的组合，以及 有机会确定分子特征，以确定将从这些活动中受益的种群 组合。通过精选课程和讲习班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 对当前概念和技术的理解，对项目结果的持续反馈，以及 进步，以及更多地接触到更多的翻译工作。总体而言，研究和培训计划将 提供坚实的基础，在此基础上建立一个多产的，独立的癌症研究人员的职业生涯。