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

项目目标：Haricharan博士的长期职业目标是研究DNA损伤的未充分研究的作用 作为一名独立的癌症研究人员，在一所拥有 备受推崇的大学生生物医学研究项目。她在拟议项目中的目标是 理解错配修复MutL复合体基因突变对 ER+乳腺癌、结直肠癌和膀胱癌标准治疗（目标1），建立一种新的、预后不良的作用 膀胱癌和结直肠癌中MutL基因的研究（Aim 1），并找到替代靶向治疗方法， 证明在MutL缺陷型（MutL-）乳腺癌、膀胱癌和结肠直肠癌中有效（目标2）。 目标和研究方法：为了实现这些目标，目标1将调查 在ER+乳腺癌、膀胱癌和结直肠癌中发生的MLH1错义突变， 体外和体内MutL缺失的诊断测定。Haricharan博士已经证明了 ER+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抑制剂联合治疗的反应 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+乳腺癌是女性中最常见的恶性肿瘤，膀胱癌是第五位 最常见的是结直肠癌，结直肠癌是男性和女性中第三常见的癌症。在一起， 在美国，每年约有10万人死于癌症。这项研究有可能预防 高达20%的死亡病例因此，这项研究可以显著影响这三种疾病的临床管理。 致命的癌症在短期内，并推翻了研究范式的错配修复失调， 癌症类型的长期。 职业发展：拟议的工作将有助于博士Haricharan的职业发展，打破新的 地面和探索MutL损失在膀胱癌和结直肠癌中的作用，因为她以前的所有培训都 得过乳腺癌与PDX广泛合作也将有助于Haricharan博士的职业发展， 提供重要的技术专业知识。此外，实验室管理和 领导，并在此期间进行的granitarian讲习班将帮助她获得 NCI R01资助并顺利过渡到她的独立职业生涯。

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.