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.

项目总结 NCI独立职业发展之路提案的目标是请求支持 培训以开发卵巢癌的新治疗策略方面的专业知识，同时调查 共激活物相关的精氨酸甲基转移酶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阶段，K99/R00的支持将是我作为独立人士成功发展不可或缺的一部分 癌症研究人员。这份建议书中概述的培训计划将利用 维斯塔尔研究所、宾夕法尼亚大学以及坦普尔大学。我的训练也将由 成功指导了多名博士后、博士后和临床研究员的顾问委员会 在学术生涯中。 该提案的科学部分侧重于从实验上确定分子机制。 表达CARM1的卵巢癌细胞对HSP70抑制的敏感性。建议进行的研究 是基于我之前的发现，即CARM1在卵巢中经常过度表达并发挥癌基因的作用 癌症患者。高级别浆液性卵巢癌(HGSOC)CARM1扩增率最高， 在所有癌症类型中过度表达(约20%)。此外，高CARM1水平与 卵巢上皮性癌患者存活率低。因此，开发针对CARM1表达的新方法是当务之急 平等机会委员会。我的初步数据表明，表达CARM1的细胞对HSP70抑制具有选择性的敏感性。热休克蛋白70 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，热休克蛋白70是CARM1 S酶活性的底物。然而，HSP70的修饰效应 对CARM1的理解还不完全。因此，这项提案的主要目标是确定CARM1- 表达EOC可以通过基于HSP70的新的治疗策略进行治疗并最终根除 抑制力。因此，我将探索以下科学目标：1)阐明 HSP70抑制细胞对CARM1-High细胞的选择性 高表达CARM1和低表达CARM1的EoC细胞。2)开发CARM1的新治疗策略- 基于HSP70抑制的EOCs的表达。完成这项提案中的科学目标将会有所帮助 发展我在卵巢癌领域的研究技能和知识，并将为 建立HSP70抑制剂作为单一药物或与其他有希望的药物联合使用于CARM1-高EOCs 小分子抑制剂，如EZH2抑制剂。