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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：
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
项目类别：
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

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.

项目总结/文摘