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: 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
• 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

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：哈里查兰博士的长期职业目标是调查DNA损伤的未被研究的角色 在学术机构担任独立癌症研究员，修复治疗反应中的缺陷 备受好评的大学生物医学研究计划。她在提议的项目中的目标是 了解错配修复MutL复合体基因突变对反应的功能影响 ER+乳腺癌、结直肠癌和膀胱癌的标准护理(目标1)，建立一个新的、预后不良的作用 针对膀胱癌和结直肠癌的MutL基因(目标1)，并找到替代的靶向治疗方法，可以 证明对MutL缺陷(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 ER阳性乳腺癌、膀胱癌和结直肠癌中MLH1的错义突变和测试潜力 MutL丢失的体内外诊断方法。Haricharan博士已经证明了 雌激素受体阳性乳腺癌内分泌治疗抵抗中的MutL失调。哈里查兰博士之前发现 MutL-ER+乳腺癌细胞对CDK4/6抑制剂的易感性在目标2中，她将从功能上评估效果 MutL失衡对CDK4/6和BclI联合治疗反应的影响 患者来源的异种移植(PDX)和ER+乳腺癌、膀胱癌和结直肠癌的传统细胞系模型。 与NCI任务相关：ER+乳腺癌、膀胱癌和结直肠癌是 美国：ER+乳腺癌是女性最常见的恶性肿瘤，膀胱癌位居第五 最常见的是结直肠癌，在男性和女性中都是第三常见的癌症。一起， 在美国，每年约有10万人死于癌症。这项研究有可能预防 其中高达20%的死亡病例。因此，这项研究可以对这三种疾病的临床管理产生重大影响。 在短期内致命的癌症，并颠覆错配修复失调的研究范式 从长远来看，癌症的类型。 职业发展：拟议中的工作将通过创新帮助哈里查兰博士的职业发展 基础和探索MutL丢失在膀胱癌和结直肠癌中的作用，因为她之前的所有培训都 患过乳腺癌。广泛使用PDX还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，实验室管理和实验室管理的教学课程 领导力，以及在此奖项期间举办的关于授予精神的研讨会将帮助她获得 NCI R01的资金和顺利过渡到她的独立职业生涯。