Oncogenic Chromatin Remodeling and Anticancer Mechanisms

致癌染色质重塑和抗癌机制

基本信息

批准号：
10646923
负责人：
STEVEN ZHENG
金额：
$ 45.31万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646923
关键词：
ARID1A gene Antineoplastic Agents CCI-779 Cancer Biology Cancer Patient Chromatin Chromatin Remodeling Factor Clinical Complex Data Development Disease FDA approved FRAP1 gene Genetic Transcription Growth Human Knowledge Lead Malignant Neoplasms Mediating Molecular Oncogenic Oncology Outcome Pathway interactions Pharmaceutical Preparations Phosphorylation Physiology Play Protein Kinase Proteins Publishing Regulation Resistance Role SWI/SNF Family Complex Serine Signal Pathway Signal Transduction Sirolimus Somatic Mutation Testing Therapeutic Tumor Suppressor Proteins anti-cancer cancer therapy cancer type chromatin remodeling epigenetic regulation improved in vivo inhibitor public health relevance response targeted cancer therapy targeted treatment therapy resistant treatment response tumor tumorigenesis

ARID1A gene Antineoplastic Agents CCI-779 Cancer Biology Cancer Patient Chromatin Chromatin Remodeling Factor Clinical Complex Data Development Disease FDA approved FRAP1 gene Genetic Transcription Growth Human Knowledge Lead Malignant Neoplasms Mediating Molecular Oncogenic Oncology Outcome Pathway interactions Pharmaceutical Preparations Phosphorylation Physiology Play Protein Kinase Proteins Publishing Regulation Resistance Role SWI/SNF Family Complex Serine Signal Pathway Signal Transduction Sirolimus Somatic Mutation Testing Therapeutic Tumor Suppressor Proteins anti-cancer cancer therapy cancer type chromatin remodeling epigenetic regulation improved in vivo inhibitor public health relevance response targeted cancer therapy targeted treatment therapy resistant treatment response tumor tumorigenesis

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项目摘要

ABSTRACT The SWI/SNF chromatin remodeling complexes impart epigenetic regulation and control accessibility of chromatin to transcriptional machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. ARID1A is a component of the BAF SWI/SNF complex and a major tumor suppressor. ARID1A is inactivated by somatic mutations in a wide spectrum of cancer types. Despite the apparent importance of SWI/SNF chromatin remodelers in cancer, their regulation by growth and oncogenic signals remains not well understood. mTOR complex 1 (mTORC1) is a conserved protein kinase and a central growth controller. mTORC1 is an oncogenic driver and the target of US FDA-approved oncology drugs rapamycin and rapamycin analogs. Our preliminary data revealed that mTORC1 promotes proteasomal degradation of ARID1A protein. Moreover, ARID1A plays an important role in therapeutic response and resistance to mTORC1 inhibitors. Because mTOR pathway is estimated to be activated in nearly half of all human tumors, mTOR-dependent degradation represents a common mechanism to inactivate the ARID1A tumor suppressor in cancer. Therefore, it is important to understand the underlying regulatory mechanisms and its role in cancer biology and therapy. There are two specific aims in this application: Aim 1 will dissect the molecular mechanism by which mTORC1 regulates ARID1A and oncogenic chromatin remodeling. Aim 2 will investigate the significance of mTORC1-dependent ARID1A regulation in tumorigenesis and anticancer drug response. Our studies are anticipated to fill a knowledge gap in the regulation of the ARID1A tumor suppressor in tumorigenesis and anticancer drug response/resistance. If successful, this project could lead to better strategies to target mTOR pathway, improving clinical outcomes for cancer patients.

抽象的 SWI/SNF染色质重塑络合物赋予表观遗传调节并控制的可及性染色质到转录机械。染色质重塑在正常生理学和疾病，尤其是癌症。 ARID1A是BAF SWI/SNF复合物和主要肿瘤的组成部分抑制器。在各种癌症类型中，ARID1A被体细胞突变灭活。尽管有 SWI/SNF染色质重塑剂在癌症中的显然重要性，它们对生长和致癌的调节信号仍然不太了解。 MTOR复合物1（MTORC1）是一种保守的蛋白激酶和中央增长控制器。 MTORC1是一种致癌驱动力，也是美国FDA批准的肿瘤药物的目标雷帕霉素和雷帕霉素类似物。我们的初步数据显示MTORC1促进蛋白酶体 ARID1A蛋白的降解。此外，ARID1A在治疗反应中起重要作用，对MTORC1抑制剂的抗性。因为估计在所有人类的几乎一半中估计MTOR途径肿瘤，mTOR依赖性降解代表了使ARID1A肿瘤失活的常见机制癌症中的抑制剂。因此，了解潜在的监管机制及其作用很重要在癌症生物学和治疗中。在此应用中有两个具体的目标：AIM 1将剖析分子 MTORC1调节ARID1A和致癌染色质重塑的机制。 AIM 2将调查 MTORC1依赖性ARID1A调节在肿瘤发生和抗癌药物反应中的重要性。我们的预计研究会填补肿瘤发生中ARID1A抑制剂调节的知识空白和抗癌药物反应/抗性。如果成功，该项目可能会导致更好的策略来针对MTOR 途径，改善癌症患者的临床结局。