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: 10682656
• 负责人: Sergey Karakashev
• 金额: $ 24.9万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682656
• 关键词: 3-Dimensional; ATP phosphohydrolase; Advisory Committees; Antineoplastic Agents; Apoptosis; Arginine; 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; base; brca gene; 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; loss of function; migration; mouse model; mutant; novel strategies; novel therapeutic intervention; overexpression; patient derived xenograft model; 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.

项目概要 此 NCI 独立职业发展之路提案的目标是请求支持 培训以培养开发卵巢癌新治疗策略的专业知识，同时研究 共激活剂相关精氨酸甲基转移酶 1 (CARM1) 在促进对 HSP70 抑制的敏感性中的作用。 在我职业生涯的这一部分中，K99/R00 支持对于我作为独立人士的成功发展至关重要 癌症研究员。本提案中概述的培训计划将利用以下方面的广泛资源： 威斯塔研究所、宾夕法尼亚大学以及天普大学。我的训练也将受到 咨询委员会成功指导了多名博士前、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 表达 CARM1 的卵巢癌细胞对 HSP70 抑制的敏感性。拟议的研究 基于我之前的发现，即 CARM1 在卵巢中经常过度表达并充当癌基因 癌症患者。高级别浆液性卵巢癌 (HGSOC) 的 CARM1 扩增率最高，且 在所有癌症类型中过度表达（合计约 20%）。此外，高 CARM1 水平与 EOC 患者的生存率较差。因此，开发针对 CARM1 表达的新方法势在必行。 经济合作委员会。我的初步数据表明 CARM1 表达细胞对 HSP70 抑制选择性敏感。热休克蛋白70 是蛋白质折叠机制的重要组成部分，其水平在多种类型的癌症中上调。 有趣的是，HSP70 是 CARM1 酶活性的底物。然而，HSP70修饰的效果 CARM1 尚未完全理解。因此，该提案的主要目标是确定 CARM1- 表达 EOC 可以通过基于 HSP70 的新型治疗策略进行治疗并最终根除 抑制。因此，我将探索以下科学目标：1）阐明其背后的机制基础 通过使用功能获得和丧失检测，通过 HSP70 抑制对 CARM1-high 细胞进行选择性 CARM1 高表达和 CARM1 低表达的 EOC 细胞。 2) 为CARM1-开发新的治疗策略 基于 HSP70 抑制表达 EOC。本提案中科学目标的完成将有助于 发展我在卵巢癌领域的研究技能和知识，并将为我的研究奠定重要基础 确定 HSP70 抑制剂在 CARM1 高 EOC 中作为单一药物或与其他有前途的药物联合使用 小分子抑制剂，例如 EZH2 抑制剂。