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

基本信息

批准号：
10534744
负责人：
Kelley McQueeney
金额：
$ 7.38万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-01-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534744
关键词：
Affect Animal Experimentation 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 Dimerization Disease Doxorubicin Drug Combinations Educational workshop Ensure Environment Excision Exposure to Feedback Foundations Genetic Goals Grant Hour Human Immunoprecipitation Laboratories 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 Paclitaxel Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phenotype Platinum Poly(ADP-ribose) Polymerase Inhibitor Population Primary Neoplasm Probability Productivity Proteins Recurrent disease Regimen Research Research Personnel Resistance Sampling Solid Neoplasm Techniques Technology Testing Training Tumor Cell Line United States Validation Woman Work Xenograft Model cancer cell cancer therapy carcinogenesis career cell killing chemotherapeutic agent chemotherapy combinatorial cytotoxic drug action drug candidate high throughput screening improved in vivo innovation meetings mimetics neoplastic cell novel novel strategies novel therapeutics ovarian neoplasm patient derived xenograft model patient population patient response pharmacologic 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

项目摘要

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/摘要卵巢癌是女性总体癌症死亡的第五个主要原因。最近的估计表明今年将诊断出20,000多个新病例，将近14,000名妇女将死于仅在2019年，美国疾病。基于铂金的护理标准的细胞毒性方案在很大程度上保持在过去的15年中停滞不前，经常性疾病经常抗铂。尽管最近有一些使用分子靶向剂和维持疗法（例如PARP抑制剂）的成功，遗传复杂性和缺乏常见的分子驱动因素使预测患者反应变得困难。另外，在复发患者，癌症疗法诱导的分子变化是多方面的。结合多种药物治疗卵巢癌可能是克服这种肿瘤内异质性和获得的抵抗力可以实现更耐用的临床反应。为了利用该提案批准并显示患者的福利，旨在确定可以使细胞敏感的化合物凋亡与三种在卵巢癌疗法中充当基石的药物之一相结合时：卡铂，PARP抑制剂Olaparib和阿霉素。在第一个目标中，新颖的高通量筛选称为高通量动态BH3分析的平台将用于确定24小时的Ex vivo 化学处理使肿瘤细胞对线粒体介导的细胞凋亡敏感。这将使用三种卵巢癌模型：（1）来自原发性腹水粉末液的新鲜分离的肿瘤细胞，（2）类器官源自原发性肿瘤和（3）卵巢肿瘤细胞系的培养物。初步数据表明BH3 模仿药物与护理药物的标准相结合可以增加凋亡诱导。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，线粒体和分子水平确定哪些细胞环境可能受益于特定的BH3模拟组合。在第三个也是最后一个目标化合物中，发现组合的凋亡诱导在最近开发的患者衍生的Luciferized中，将测试三种护理药物的标准中的每一个卵巢癌的肿瘤异种移植模型。这将提供特定药物能力的体内验证组合引起肿瘤回归。这种创新的方法既具有识别有效的潜力用于铂敏感，对PARP敏感和抗铂的设置的组合，以及确定可以识别可以从中受益的人群的分子特征的机会组合。通过精选课程和研讨会来补充提案的研究部分，参与研究会议和研讨会，以及参加科学会议将确保了解当前的概念和技术，关于项目结果的不断反馈和进步，并增强了对更多翻译工作的接触。总的来说，研究和培训计划将为建立富有生产力的独立癌症研究人员的职业提供了坚实的基础。