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
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9583001
• 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; 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; Muscle; 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; novel; outcome forecast; predicting response; prevent; prognostic; programs; response; standard of care; targeted treatment; therapy resistant; treatment response; tumor

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调查DNA损害的研究不足的角色 在学术机构中，治疗反应的维修缺陷是 备受赞誉和大学生物医学研究计划。她在拟议项目中的目标是 了解突变在MUTL复合物的基因中的功能影响不匹配修复对响应的反应 ER+乳腺癌，结直肠癌和膀胱癌（AIM 1）中的标准护理（AIM 1），建立了一种新颖的预后作用 对于膀胱和大肠癌中的MUTL基因（AIM 1），并找到可以替代的靶向疗法 在MUTL缺陷（MUTL-）乳腺癌，膀胱和结直肠癌（AIM 2）中证明有效。 目的和研究方法：为了实现这些目标，目标1将研究 在ER+乳房，膀胱和结直肠癌中发生的MLH1的错义突变，并测试潜力 体外和体内MUTL损失的诊断测定。 Haricharan博士已经表现出了因果关系 ER+乳腺癌的内分泌疗法耐药性中的MUTL失调。 Haricharan博士以前确定 Mutler+乳腺癌细胞对CDK4/6抑制剂的脆弱性。在AIM 2中，她将在功能上评估效果 在临床信息丰富的信息中，对组合CDK4/6和BCL抑制剂疗法的反应的MUTL失调 患者衍生的异种移植物（PDX）和ER+乳腺癌，膀胱和大肠癌的传统细胞系模型。 与NCI任务相关：ER+乳房，膀胱和大肠癌是最常见的三种癌症 美国：ER+乳腺癌是女性中最常见的恶性肿瘤，而膀胱癌是第五个 最常见的结直肠癌是男性和女性中第三大常见的癌症。一起， 他们每年在美国造成约100,000次与癌症有关的死亡。这项研究有可能预防 这些死亡中最多有20％。因此，这项研究可以显着影响这三个的临床管理 在短期内致命癌症，并推翻了整个不匹配修复失调的研究范例 从长远来看癌症类型。 职业发展：拟议的工作将通过破坏新的新作品来帮助Harichan博士的职业发展 地面并探索MUTL丧失在膀胱和结直肠癌中的作用，因为她以前的所有训练都有 患有乳腺癌。与PDXS广泛合作还将帮助Haricharan博士的职业发展。 提供重要的技术专长。此外，实验室管理中的教学课程和 领导和关于在本奖项期间进行的授予技巧的讲习班将有助于她获得 NCI R01的资金和过渡顺利进入她的独立职业。