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 损伤中未被充分研究的作用 作为学术机构中的独立癌症研究员，修复治疗反应中的缺陷 备受推崇的大学生物医学研究项目。她在拟议项目中的目标是 了解错配修复 MutL 复合体基因突变对响应的功能影响 ER+ 乳腺癌、结直肠癌和膀胱癌的护理标准（目标 1），建立了新颖的不良预后作用 针对膀胱癌和结直肠癌中的 MutL 基因（目标 1），并找到可替代的靶向治疗方法 证明对 MutL 缺陷型 (MutL-) 乳腺癌、膀胱癌和结直肠癌有效（目标 2）。 目标和研究方法：为了实现这些目标，目标 1 将调查功能影响 ER+乳腺癌、膀胱癌和结直肠癌中发生的 MLH1 错义突变以及测试潜力 体外和体内 MutL 丢失的诊断测定。 Haricharan 博士已经证明了其因果关系 ER+ 乳腺癌内分泌治疗耐药中的 MutL 失调。 Haricharan 博士之前发现 MutL-ER+乳腺癌细胞对CDK4/6抑制剂的脆弱性。在目标 2 中，她将从功能上评估效果 MutL 失调对 CDK4/6 和 Bcl 抑制剂组合治疗反应的临床信息 患者来源的异种移植物 (PDX) 和 ER+ 乳腺癌、膀胱癌和结直肠癌的传统细胞系模型。 与 NCI 使命的相关性：ER+ 乳腺癌、膀胱癌和结直肠癌是美国最常见的三种癌症 美国：ER+乳腺癌是女性最常见的恶性肿瘤，膀胱癌排名第五 最常见的癌症，结直肠癌是男性和女性中第三大最常见的癌症。一起， 美国每年约有 10 万人因癌症相关死亡。这项研究有可能预防 高达 20% 的死亡。因此，这项研究可以显着影响这三种疾病的临床管理 短期内致命的癌症，并颠覆了错配修复失调的研究范式 从长远来看，癌症类型。 职业发展：拟议的工作将通过突破新的领域来帮助 Haricharan 博士的职业发展 基础并探索 MutL 缺失在膀胱癌和结直肠癌中的作用，因为她之前的所有训练都 曾患乳腺癌。与 PDX 的广泛合作也将通过以下方式帮助 Haricharan 博士的职业发展： 提供重要的技术专长。此外，实验室管理和 领导力以及在该奖项期间举办的赠款研讨会将帮助她获得 NCI R01 资助并顺利过渡到她的独立职业生涯。