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

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

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Svasti Haricharan其他文献

Svasti Haricharan的其他文献

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{{ truncateString('Svasti Haricharan', 18)}}的其他基金

Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
  • 批准号:
    10737565
  • 财政年份:
    2023
  • 资助金额:
    $ 14.72万
  • 项目类别:
Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
  • 批准号:
    10998271
  • 财政年份:
    2023
  • 资助金额:
    $ 14.72万
  • 项目类别:
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
  • 批准号:
    9583001
  • 财政年份:
    2018
  • 资助金额:
    $ 14.72万
  • 项目类别:
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
  • 批准号:
    9765215
  • 财政年份:
    2018
  • 资助金额:
    $ 14.72万
  • 项目类别:

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