Novel Mechanisms of MED12-TGFbeta-mediated resistance to PARP Inhibitors in BRCA-deficient Cancer Cells

MED12-TGFbeta 介导的 BRCA 缺陷癌细胞对 PARP 抑制剂耐药的新机制

基本信息

批准号：
10536964
负责人：
Lindsey Marie Pale
金额：
$ 3.34万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536964
关键词：
Address Antineoplastic Agents Architecture Aspergillus Nuclease S1 BARD1 gene BRCA deficient BRCA1 gene BRCA2 gene Binding Biological Assay Breast Cancer Cell Bromodeoxyuridine Cancer Patient Cells Chemoresistance Cisplatin Clinic Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Cryoelectron Microscopy DNA Repair DNA Repair Gene DNA replication fork Data Development Disease remission Double Strand Break Repair Drug resistance Exposure to Fiber Gene Expression Genetic Determinism Genetic Screening Genome Stability Genomic Instability Genomics Goals Hela Cells Knock-out Knowledge Laboratories Light Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mediating Mediator of activation protein Medicine Mentorship Oncology PALB2 gene Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Play Publications Publishing Research Resistance Resources Role Sampling Scientist Signal Pathway Small Interfering RNA Structure Techniques Testing Therapeutic Transforming Growth Factor beta Work alkalinity anticancer research cancer cell cancer therapy clinically relevant college experience genome-wide graduate student homologous recombination hydroxyurea inhibitor leukemia malignant breast neoplasm mutant novel novel therapeutic intervention particle protein complex protein expression repaired resistance mechanism response restoration skills therapy resistant

项目摘要

Project Summary This F31 application focuses on characterizing a novel resistance mechanism for PARP inhibitors. I am requesting support for developing a project which I have previously initiated and published on. This proposal addresses a fundamental gap in knowledge and could significantly impact cancer therapeutic strategies and cancer patient survival. Moreover, the resources this application would provide would greatly impact my development as a graduate student and independent scientist. This proposal would allow me the opportunity to be exposed to state-of-the-art laboratory techniques including genomic sequencing and cryo-EM. This would provide me with a complex mix of critical skills that will be important for my development into a well-rounded scientist, and for which are highly attainable due to the support and resources provided by my mentorship team and at Penn State College of Medicine. In this proposal, I focus on elucidating the mechanisms by which MED12 and TGFb mediate resistance to PARP inhibitors. I previously showed loss of MED12 confers resistance to PARP inhibitors in BRCA-deficient cells via activation of the TGFb pathway. This resistance was underscored by an increase in homologous recombination DNA repair efficiency and replication fork stability following TGFb pathway activation in BRCA-deficient cells. Here, I hope to expand on this research to further define the mechanism behind this chemoresistance, to reduce this gap in knowledge, and to gain experience and expertise in the rapidly growing field of structural oncology in cancer research. To investigate the role of MED12 and TGFb in chemoresistance further, I will explore three aims: 1) Investigate specific interactions between MED12 with the Mediator complex and TGFbR2 and the impact of these interactions on chemosensitivity in BRCA-deficient cells, 2) determine the role of ssDNA gap suppression in MED12-TGFb-mediated chemoresistance and genomic stabilization, and 3) investigate the impact of TGFb activation on the structure of mutant BRCA1 in patient-derived HCC1937 breast cancer cells. Achieving these aims will expand my knowledge in the field of DNA damage and repair and expose me to cutting-edge new techniques in the field of structural oncology. Thus, this work will advance my personal goals, and significantly impact the field by providing new information on chemosensitivity in patients harboring BRCA-mutant cancers.

项目概要该 F31 应用的重点是表征 PARP 抑制剂的新型耐药机制。我是请求支持开发我之前发起并发布的项目。这个提议解决了知识方面的根本差距，可能会显着影响癌症治疗策略和癌症患者的生存率。此外，该应用程序提供的资源将极大地影响我作为研究生和独立科学家的发展。该提案将使我有机会接触最先进的实验室技术，包括基因组测序和冷冻电镜。这会为我提供复杂的关键技能组合，这对于我发展成为全面发展的人非常重要科学家，由于我的导师团队提供的支持和资源，这是非常容易实现的和宾夕法尼亚州立大学医学院。在本提案中，我重点阐述 MED12 和 TGFb 介导 PARP 耐药性的机制抑制剂。我之前通过 TGFb 途径的激活。同源重组的增加强调了这种抵抗力 BRCA 缺陷细胞中 TGFb 通路激活后的 DNA 修复效率和复制叉稳定性。在这里，我希望扩展这项研究，进一步明确这种化学耐药性背后的机制，以减少弥补知识差距，并在快速发展的结构肿瘤学领域获得经验和专业知识癌症研究。为了进一步研究 MED12 和 TGFb 在化疗耐药中的作用，我将探讨三个目标：1) 研究 MED12 与介体复合物和 TGFbR2 之间的特定相互作用以及这些相互作用的影响 BRCA 缺陷细胞中化学敏感性的相互作用，2) 确定 ssDNA 间隙抑制在 MED12-TGFb 介导的化疗耐药性和基因组稳定性，以及 3) 研究 TGFb 的影响患者来源的 HCC1937 乳腺癌细胞中突变 BRCA1 结构的激活。实现这些目标将扩展我在 DNA 损伤和修复领域的知识，并使我接触到前沿的新知识结构肿瘤学领域的技术。因此，这项工作将推进我的个人目标，并显着通过提供有关 BRCA 突变癌症患者化疗敏感性的新信息来影响该领域。