Targeting cell cycle dysregulation in GIST

针对 GIST 细胞周期失调

基本信息

批准号：
10163817
负责人：
Inga-Marie Schaefer
金额：
$ 28.55万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163817
关键词：
14q Address Advisory Committees Behavior Benign Biological Biology CDK4 gene CRISPR screen Cancer Model Cell Cycle Cell Survival Chromosome Deletion Clinical Clinical Trials Collaborations Combined Modality Therapy DNA Dependence Development Diagnosis Diagnostic Discipline Disease Disease Progression Disease Resistance Down-Regulation Drug resistance Environment Evaluation Event FDA approved FRAP1 gene Fostering Frequencies Future Gastrointestinal Stromal Tumors Gene Fusion Genes Genetic Genetic Transcription Genomics Goals Home Hospital Departments Hospitals Human Image In Vitro International K-Series Research Career Programs Knowledge Lead Leadership Malignant - descriptor Malignant Neoplasms Mediating Medical Mentors Mentorship Mesenchymal Cell Neoplasm Microscopic Modeling Mutation Neoplasm Metastasis Oncogenic PDGFRA gene Pathology Pathway interactions Patients Pharmaceutical Preparations Physicians Positioning Attribute Proteomics RB1 gene Recurrence Research Research Project Summaries Resistance Resolution Role Scientist Surgical Oncology Testing Therapeutic Time Training Translational Research Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Unresectable Validation Woman advanced disease base career career development cell growth clinical practice gain of function mutation gene repression genome-wide improved in vivo in vivo Model inhibitor/antagonist innovation insight neoplastic cell novel novel therapeutics patient derived xenograft model pre-clinical preclinical evaluation preclinical study programs research study resistance mutation response sarcoma tenure track treatment response tumor tumor progression virtual

项目摘要

PROJECT SUMMARY Research: Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal neoplasms. Most GISTs are initiated by KIT or PDGFRA gain-of-function mutations which are therefore already found in microscopic forms of GISTs. During progression to aggressive disease, early GISTs acquire a canonical sequence of chromosomal deletions including 14q deletions that inactivate MAX, fostering cell cycle dysregulation through p16 transcriptional repression. Genomic mutations that directly inactivate p16 and other cell cycle regulators occur at subsequent stages in progression. While tyrosine kinase inhibitor (TKI) therapies for advanced GISTs result in dramatic clinical responses, secondary TKI resistance often leads to fatal disease progression, highlighting the need for novel targets defined by biologic vulnerabilities, particularly aberrations present across the entire metastatic burden in a given patient. The objective of this mentored research career development proposal is to characterize the events in GIST genomic progression that lead to incremental cell cycle dysregulation, particularly aberrations impacting p16/CDK4/RB1, with the goal of developing novel therapies for patients with advanced GIST. Leveraging GIST as a unique model amongst sarcomas to study genomic progression, my Aim 1 studies address the hypothesis that cell cycle perturbations, including targetable aberrations of the p16/CDK4/RB1 pathway, are virtually universal events in advanced GIST. The Aim 2 studies are motivated by my hypothesis that GIST responses to CDK4/6-inhibition will be maximized by combination approaches. These studies use genome-wide CRISPR screens to identify synthetic lethals with CDK4/6-inhibition in GIST. The Aim 3 studies are preclinical in vitro and in vivo validations of combination therapies that might increase GIST response to CDK4/6 inhibition. Candidate Career Goals: To expedite these translational research studies, I will foster international collaborations with experts in sarcoma genomics, biology, pathology, medical/surgical oncology, and scientific innovation. The studies encompassed by this career development award will be critical to obtain the training, knowledge, and expertise needed to successfully establish an independent translational sarcoma research program and apply for a tenure-track physician-scientist position in academic pathology. The proposed research will be performed under the mentorship of Dr. Jonathan A. Fletcher, leader of two international GIST research consortia, with guidance from an interdisciplinary Scientific Advisory Committee composed of leading experts in the sarcoma field. Environment: Brigham and Women’s Hospital (BWH) houses internationally recognized research programs in scientific discovery training physician-scientists for leadership roles in translational research. The BWH Department of Pathology is home to global leaders in sarcoma/GIST diagnostics, biology, and genetics, who collaborate effectively with clinical disciplines to leverage scientific discoveries into clinical practice for improved diagnosis and treatment.

项目摘要研究：胃肠道肿瘤（GIST）是最常见的间充质肿瘤之一。大多数GIST是由套件或PDGFRA功能收益突变引发的，因此已经在大要素的微观形式。在发展为侵略性疾病期间，早期的GIST获得了规范染色体缺失的序列，包括14Q缺失，使最大灭活，促进细胞周期通过p16转录表示的失调。直接使p16和其他直接活化的基因组突变细胞周期调节剂发生在随后的进展阶段。而酪氨酸激酶抑制剂（TKI）疗法对于先进的GIST会导致急剧的临床反应，次级TKI耐药性通常会导致致命疾病进步，强调了对生物学脆弱性定义的新颖目标的需求，尤其是畸变在给定患者中存在整个转移性燃烧。这项修改研究生涯的目的开发建议是表征GIST基因组进展中的事件，导致细胞增量周期失调，尤其是影响p16/cdk4/rb1的畸变，目的是开发新颖患有高级要点的患者的疗法。利用要点作为肉瘤中的独特模型来研究基因组进步，我的目标1研究解决了细胞周期扰动的假设，包括 p16/cdk4/rb1途径的靶向像差实际上是高级要点中的通用事件。这 AIM 2研究是由我的假设激励的，即要点对CDK4/6抑制作用的反应将被最大化组合方法。这些研究使用全基因组CRISPR筛选来识别与 GIST中的CDK4/6抑制作用。 AIM 3研究是临床前的体外和组合验证可能会增加对CDK4/6抑制作用的GIST反应的疗法。候选职业目标：加快这些翻译研究，我将与肉瘤基因组专家培养国际合作，生物学，病理学，医学/外科肿瘤学和科学创新。这些研究包含在其中职业发展奖对于获得所需的培训，知识和专业知识至关重要成功建立独立的翻译肉瘤研究计划并申请终身制医师科学家在学术病理学中的立场。拟议的研究将在两个国际观点研究联盟的负责人乔纳森·弗莱彻（Jonathan A. Fletcher）博士的遗产。来自由肉瘤领域的主要专家组成的跨学科科学咨询委员会。环境：杨百翰妇女医院（BWH）在国际公认的研究计划中科学发现培训训练物理科学家在转化研究中的领导角色。 BWH 病理学系是肉瘤/GIST诊断，生物学和遗传学的全球领导者的所在地，谁是谁与临床学科有效合作，将科学发现用于临床实践改进的诊断和治疗。