Targeting cell cycle dysregulation in GIST

针对 GIST 细胞周期失调

• 批准号: 9805478
• 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
• 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/9805478
• 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 environment; 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 Initiators; 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; pre-clinical; preclinical evaluation; preclinical study; programs; research study; resistance mutation; response; sarcoma; tenure track; treatment response; tumor; tumor progression; virtual

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.

项目概要 研究：胃肠道间质瘤（GIST）是最常见的间叶性肿瘤之一。 大多数 GIST 是由 KIT 或 PDGFRA 功能获得性突变引发的，因此这些突变已在 GIST 的微观形式。在进展为侵袭性疾病的过程中，早期 GIST 获得了典型的 染色体缺失序列，包括使 MAX 失活、促进细胞周期的 14q 缺失 通过 p16 转录抑制而失调。直接使 p16 和其他基因失活的基因突变 细胞周期调节因子出现在进展的后续阶段。虽然酪氨酸激酶抑制剂（TKI）疗法 对于晚期 GIST 会产生显着的临床反应，继发性 TKI 耐药通常会导致致命疾病 进展，强调需要由生物脆弱性，特别是畸变定义的新目标 存在于特定患者的整个转移负担中。这个指导研究生涯的目标 开发提案旨在描述 GIST 基因组进展中导致细胞增量的事件 周期失调，特别是影响 p16/CDK4/RB1 的畸变，目标是开发新的 晚期 GIST 患者的治疗方法。利用 GIST 作为肉瘤中的独特模型进行研究 基因组进展，我的目标 1 研究提出了细胞周期扰动的假设，包括 p16/CDK4/RB1 通路的可靶向畸变实际上是晚期 GIST 中的普遍事件。这 目标 2 研究的动机是我的假设，即 GIST 对 CDK4/6 抑制的反应将通过以下方式最大化： 组合方法。这些研究使用全基因组 CRISPR 筛选来识别合成致死细胞 GIST 中的 CDK4/6 抑制。 Aim 3 研究是组合的临床前体外和体内验证 可能会增加 GIST 对 CDK4/6 抑制的反应的疗法。候选人的职业目标：加快实现这些目标 转化研究，我将促进与肉瘤基因组学专家的国际合作， 生物学、病理学、医学/肿瘤外科和科学创新。本研究涵盖的研究 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 成功建立独立的转化肉瘤研究项目并申请终身教职 学术病理学中的医师科学家地位。拟议的研究将在 两个国际 GIST 研究联盟领导者 Jonathan A. Fletcher 博士的指导 来自由肉瘤领域领先专家组成的跨学科科学咨询委员会。 环境：布莱根妇女医院 (BWH) 拥有国际认可的研究项目 科学发现培训医师科学家在转化研究中发挥领导作用。身体健康中心 病理科是肉瘤/胃肠道间质瘤诊断、生物学和遗传学领域全球领导者的所在地，他们 与临床学科有效合作，将科学发现应用于临床实践 改善诊断和治疗。