Targeting HSP70 in CARM1-expressing epithelial ovarian cancer

靶向表达 CARM1 的上皮性卵巢癌中的 HSP70

• 批准号: 9977463
• 负责人: Sergey Karakashev
• 金额: $ 11.9万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977463
• 关键词: 3-Dimensional; ATP phosphohydrolase; Advisory Committees; Antineoplastic Agents; Apoptosis; Arginine; BRCA1 gene; Biological Assay; Cancer Patient; Cancer cell line; Cell Culture Techniques; Cells; Cessation of life; Clinical; Data; Development; Dimensions; Disease; Down-Regulation; EZH2 gene; Epigenetic Process; Epithelial ovarian cancer; Foundations; Gene Expression; Genes; Goals; Growth; Heat Shock 70kD Protein Binding Protein; Heat-Shock Proteins 70; In Vitro; Knock-out; Knowledge; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mentors; Methylation; Methyltransferase; Modification; Molecular; Mutation; Oncogenes; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Pennsylvania; Pre-Clinical Model; Protein-Arginine N-Methyltransferase; Proteins; Research; Research Personnel; Resources; Role; Serous; Site; Site-Directed Mutagenesis; Specificity; Testing; The Wistar Institute; Training; Training Support; Tumor Suppression; United States; Universities; Xenograft procedure; base; cancer cell; cancer type; career; career development; clinically relevant; coactivator-associated arginine methyltransferase 1; experimental study; genetic makeup; genome-wide analysis; heat-shock proteins 40; in vivo; in vivo Model; inhibitor/antagonist; loss of function; migration; mouse model; mutant; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; pre-doctoral; protein folding; skills; small molecule inhibitor; small molecule libraries; targeted treatment; tumor; two-dimensional

PROJECT SUMMARY The goals of this NCI Pathway to Independence Career Development proposal are to request support for training to develop expertise in developing novel therapeutic strategies for ovarian cancer while investigating the role of coactivator-associated arginine methyltransferase 1 (CARM1) in promoting sensitivity to HSP70 inhibition. K99/R00 support during this part of my career will be integral to my successful development as an independent cancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources at The Wistar Institute, University of Pennsylvania as well as Temple University. My training will also be guided by the advisory committee who have successfully mentored multiple predoctoral, postdoctoral, and clinical fellows in academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanism underlying the sensitivity of CARM1-expresing ovarian cancer cells to HSP70 inhibition. The proposed studies are based on my previous findings that CARM1 is often overexpressed and functions as an oncogene in ovarian cancer patients. High-grade serous ovarian cancer (HGSOC) has the highest rate of CARM1 amplification and overexpression (~20% combined) among all cancer types. Moreover, high CARM1 levels are associated with poor survival in EOC patients. Thus, it is imperative to develop novel approaches to target CARM1-expressing EOC. My preliminary data suggest CARM1-expressing cells are selectively sensitive to HSP70 inhibition. HSP70 is a crucial part of the protein folding machinery and its levels are upregulated in multiple types of cancer. Interestingly, HSP70 is a substrate for CARM1’s enzymatic activity. However, the effect of HSP70 modification by CARM1 is not fully understood. Thus, the major goal of this proposal is to determine whether CARM1- expressing EOC can be treated and ultimately eradicated by novel therapeutic strategies based on HSP70 inhibition. Therefore, I will explore the following scientific aims: 1) To elucidate the mechanistic basis underlying the selectivity against CARM1-high cells by HSP70 inhibition by using gain and loss of function assays in CARM1-high and CARM1-low expressing EOC cells. 2) To develop novel therapeutic strategies for CARM1- expressing EOCs based on HSP70 inhibition. The completion of the scientific aims in this proposal will help develop my research skills and knowledge in the field of ovarian cancer and will lay a critical foundation to establish the use HSP70 inhibitors in CARM1-high EOCs as a single agent or in combination with other promising small-molecule inhibitors such as EZH2 inhibitors.

项目摘要 本NCI独立职业发展之路提案的目标是请求支持， 培训，以发展开发卵巢癌新治疗策略的专业知识，同时研究 辅激活因子相关精氨酸甲基转移酶1（CARM 1）在促进对HSP 70抑制的敏感性中的作用。 在我职业生涯的这一阶段，K99/R 00的支持将是我作为独立员工成功发展的不可或缺的一部分 癌症研究员本提案中概述的培训计划将利用 威斯塔研究所、宾夕法尼亚大学和坦普尔大学。我的训练也将遵循 咨询委员会成功地指导了多个博士前，博士后和临床研究员 在学术生涯中。 该提案的科学部分侧重于通过实验确定分子机制 这是表达CARM 1的卵巢癌细胞对HSP 70抑制的敏感性的基础。拟议的研究 基于我以前的发现，CARM 1在卵巢癌中经常过度表达，并作为癌基因发挥作用。 癌症患者。高级别浆液性卵巢癌（HGSOC）的CARM 1扩增率最高， 在所有癌症类型中的过度表达（约20%组合）。此外，高CARM 1水平与以下因素相关： EOC患者生存率低。因此，迫切需要开发靶向CARM 1表达的新方法， 平等机会委员会我的初步数据表明，表达CARM 1的细胞对HSP 70抑制选择性敏感。Hsp70 是蛋白质折叠机制的关键部分，其水平在多种类型的癌症中上调。 有趣的是，HSP 70是CARM 1酶活性的底物。然而，HSP 70修饰的效果 第一，没有完全理解。因此，本提案的主要目标是确定CARM 1- 表达EOC可以通过基于HSP 70的新的治疗策略来治疗并最终根除 抑制作用因此，我将探讨以下科学目标：1）阐明其背后的机制基础 通过使用功能获得和丧失测定，通过HSP 70抑制对CARM 1高细胞的选择性， CARM 1-高和CARM 1-低表达的EOC细胞。2)为了开发针对CARM 1的新的治疗策略， 基于HSP 70抑制表达EOCs。完成这项建议的科学目标将有助于 发展我在卵巢癌领域的研究技能和知识，并将奠定关键基础， 确定HSP 70抑制剂在CARM 1-高EOC中作为单一药物或与其他有前途的药物组合使用 小分子抑制剂如EZH 2抑制剂。