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The roles of anti-apoptotic proteins BCL-XL and MCL1 in mediating survival of high-grade serous ovarian cancer following drug-induced DNA damage

抗凋亡蛋白 BCL-XL 和 MCL1 在介导药物诱导 DNA 损伤后高级别浆液性卵巢癌生存中的作用

基本信息

批准号：
10653887
负责人：
Elizabeth Harmon Stover
金额：
$ 18.47万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSOC) is often diagnosed at an advanced stage and has a poor prognosis. Although many patients initially respond to platinum and paclitaxel chemotherapy, most patients develop recurrent disease that is resistant to chemotherapy. Chemotherapy resistance is an unmet therapeutic need in HGSOC. To address this challenge, Dr. Stover performed systematic functional genomic screens to identify mediators of platinum and paclitaxel resistance. Anti-apoptotic proteins that protect cells from apoptotic cell death were strongly associated with chemotherapy resistance. Conversely, targeted drugs that inhibit anti-apoptotic proteins BCL-XL and MCL1 sensitized HGSOC cells to chemotherapy. In this proposal, Dr. Stover will test the hypothesis that BCL-XL and MCL1 are key mediators of HGSOC survival following chemotherapy-induced DNA damage. Aim 1 will determine whether BCL-XL and MCL1 inhibitors increase apoptosis when combined with DNA-damaging chemotherapy in HGSOC cell lines and patient cells, and explore effects of DNA-damaging agents on BCL-XL and MCL1 interactions with pro-apoptotic proteins. Aim 2 will assess whether the DNA damage repair capacity of HGSOC cells affects their dependency upon BCL-XL and MCL1 for survival. A chemical screen will aim to identify DNA-damaging agents and other drugs that synergize with BCL-XL and MCL1 inhibitors to kill HGSOC cells. Aim 3 will evaluate the role of BCL-XL and MCL1 in the survival of chemotherapy-resistant HGSOC. Combinations of BCL-XL and MCL1 inhibitors and chemotherapy will be tested in HGSOC cell lines with empiric platinum resistance in vitro, and HGSOC cell-line xenografts and patient-derived xenografts in vivo. Finally, we will use genomic and proteomic approaches to analyze patient samples of untreated and chemotherapy-resistant HGSOC for changes in BCL-XL and MCL1 and related anti-apoptotic proteins, as well as other chemotherapy resistance pathways. In summary, this study will assess the requirement for BCL-XL and MCL1 in HGSOC chemotherapy resistance, and begin to elucidate the crosstalk between apoptosis and DNA damage repair pathways in resistance. Combinations of BCL-XL or MCL1 inhibitors with DNA-damaging agents may be effective therapies for HGSOC. Dr. Stover's long-term goal is to contribute to new treatment options for patients with ovarian cancer through independent research focusing on ovarian cancer biology, genomics, and therapeutics. The pursuit of this goal will be facilitated by the outstanding institutional environment of the Dana-Farber Cancer Institute and accomplished mentors, including Drs. Matthew Meyerson, MD PhD and Anthony Letai, MD PhD. Collaborations with the Broad Institute will contribute exceptional resources for clinical genomics and chemical screening, and an expert advisory committee will provide guidance on experimental design and career advancement. A research training program, including courses and mentoring in key biological topics and professional development, will support Dr. Stover's goal of an independent research career pursuing laboratory research with a clinical focus to improve outcomes in ovarian cancer.

项目总结/摘要高级别浆液性卵巢癌（HGSOC）通常在晚期诊断，预后不良。虽然许多患者最初对铂和紫杉醇化疗有反应，但大多数患者对化疗有抵抗力的复发性疾病。化疗耐药性是一种未满足的治疗需求， HGSOC。为了应对这一挑战，秸秆博士进行了系统的功能基因组筛选，铂和紫杉醇耐药的介质。保护细胞免于凋亡性细胞死亡的抗凋亡蛋白与化疗耐药性密切相关。相反，抑制抗凋亡的靶向药物蛋白BCL-XL和MCL 1使HGSOC细胞对化疗敏感。在这个提议中，秸秆博士将测试假设BCL-XL和MCL 1是化疗诱导DNA后HGSOC存活的关键介质损害目的1将确定BCL-XL和MCL 1抑制剂在与 HGSOC细胞系和患者细胞中的DNA损伤化疗，并探索DNA损伤化疗的影响。药物对BCL-XL和MCL 1与促凋亡蛋白相互作用的影响。目标2将评估DNA是否 HGSOC细胞的损伤修复能力影响它们对BCL-XL和MCL 1的存活依赖性。一化学筛选的目的是鉴定DNA损伤剂和其他与BCL-XL协同作用的药物， MCL 1抑制剂杀死HGSOC细胞。目的3将评估BCL-XL和MCL 1在肿瘤患者生存中的作用。耐化疗的HGSOC。将测试BCL-XL和MCL 1抑制剂与化疗的组合在体外具有经验性铂抗性的HGSOC细胞系，以及HGSOC细胞系异种移植物和患者来源的体内异种移植物。最后，我们将使用基因组和蛋白质组学方法来分析患者样本，未治疗和化疗耐药的HGSOC，用于BCL-XL和MCL 1的变化以及相关的抗凋亡蛋白质，以及其他化疗耐药途径。总之，本研究将评估 HGSOC化疗耐药性中BCL-XL和MCL 1的表达，并开始阐明细胞凋亡和DNA损伤修复途径。BCL-XL或MCL 1抑制剂与 DNA损伤剂可能是HGSOC的有效治疗方法。秸秆博士的长期目标是为通过专注于卵巢癌的独立研究为卵巢癌患者提供新的治疗选择生物学基因组学和治疗学这一目标的实现将得到杰出的体制机构的协助。丹娜-法伯癌症研究所的环境和成功的导师，包括马修迈耶森博士， MD PhD和Anthony Letai，MD PhD。与布罗德研究所的合作将为我们的研究做出卓越的贡献。临床基因组学和化学筛选的资源，以及专家咨询委员会将提供指导关于实验设计和职业发展研究培训计划，包括课程和指导在关键的生物课题和专业发展，将支持博士秸秆的独立研究的目标职业追求实验室研究与临床重点，以改善卵巢癌的结果。