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A pan-cancer role for MutL loss in inducing treatment resistance

MutL 缺失在诱导治疗抵抗中的泛癌作用

基本信息

批准号：
10001982
负责人：
Svasti Haricharan
金额：
$ 14.72万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001982
关键词：
Award Biological Process Biomedical Research Bladder Bladder Neoplasm Breast Cancer Cell Breast Cancer Patient CDK4 gene Cancer Biology Cancer Diagnostics Cancer Patient Cell Cycle Cell Line Cells Cessation of life Clinical Clinical Data Clinical Management Colorectal Cancer Colorectal Neoplasms Complex DNA Repair Data Defect Disease Educational workshop Endocrine Endometrial Carcinoma Estrogen receptor positive FDA approved Funding Genes Genomics Goals Growth Human In Vitro Incidence Individual Institution Laboratories Leadership MLH1 gene MSH2 gene MSH3 gene Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mammary Neoplasms Mediating Mismatch Repair Missense Mutation Mission Modeling Mutation Outcome PMS1 gene PMS2 gene Pathway interactions Patients Repair Complex Research Research Design Research Personnel Resistance Role Technical Expertise Testing Therapeutic Time Training Treatment Efficacy Up-Regulation Woman Work Xenograft procedure base cancer cell cancer type career career development combinatorial diagnostic assay gene repair hormone therapy in vivo inhibitor/antagonist interest loss of function malignant breast neoplasm men muscle invasive bladder cancer novel outcome forecast predicting response prevent prognostic programs response standard of care targeted treatment therapy resistant treatment response tumor

项目摘要

Project objectives: Dr. Haricharan's long-term career goal is to investigate understudied roles for DNA damage repair defects in treatment response as an independent cancer researcher in an academic institution with a well-regarded and collegial biomedical research program. Her objective in the proposed project is to understand the functional impact of mutations in genes of the MutL complex of mismatch repair on response to standard-of-care in ER+ breast, colorectal and bladder cancer (Aim 1), establish a novel, poor prognostic role for MutL genes in bladder and colorectal cancer (Aim 1), and find alternative targeted therapeutics that can prove efficacious in MutL-defective (MutL-) breast, bladder and colorectal cancer (Aim 2). Aims and research approach: To achieve these objectives, Aim 1 will investigate the functional impact of missense mutations in MLH1 that occur in ER+ breast, bladder and colorectal cancer, and test potential diagnostic assays for MutL loss in vitro and in vivo. Dr. Haricharan has already demonstrated a causal role for MutL dysregulation in endocrine therapy resistance of ER+ breast cancer. Dr. Haricharan previously identified vulnerability of MutL- ER+ breast cancer cells to CDK4/6 inhibitors. In Aim 2, she will functionally assess effect of MutL dysregulation on response to combinatorial CDK4/6 and Bcl inhibitor therapy in clinically informative patient-derived xenografts (PDXs) and traditional cell line models of ER+ breast, bladder and colorectal cancer. Relevance to NCI mission: ER+ breast, bladder and colorectal cancer are three of the most common cancers in the US: ER+ breast cancer is the most common malignancy amongst women, and bladder cancer is the fifth most common, and colorectal cancer the third most common cancer among men and women alike. Together, they account for ~100,000 cancer-related deaths in the US every year. This study has the potential to prevent up to 20% of these deaths. Therefore, this study can significantly impact clinical management of these three lethal cancers in the short-term, and overturn the research paradigm for mismatch repair dysregulation across cancer types in the long-term. Career Development: The proposed work will help Dr. Haricharan's career development by breaking new ground and exploring the role of MutL loss in bladder and colorectal cancer, since all her previous training has been in breast cancer. Working extensively with PDXs will also aid Dr. Haricharan's career development by providing important technical expertise. Additionally, didactic courses in laboratory management and leadership, and workshops on grantsmanship undertaken during the period of this award will help her acquire NCI R01 funding and transition smoothly into her independent career.

项目目标：Haricharan博士的长期职业目标是研究DNA损伤的未被充分研究的作用