Targeting cell cycle dysregulation in GIST

项目总结 研究：胃肠道间质瘤(GIST)是最常见的间叶性肿瘤。 大多数GIST是由KIT或PDGFRA功能获得突变启动的，因此在 胃肠道间质瘤的微观形态。在发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14Q缺失，使MAX失活，促进细胞周期 P16转录抑制引起的调控失调。直接使p16等基因失活的基因组突变 细胞周期调节发生在进展的后续阶段。而酪氨酸激酶抑制剂(TKI)治疗 由于晚期GIST导致显著的临床反应，继发性TKI抵抗通常会导致致命的疾病 进展，强调需要由生物脆弱性定义的新靶点，特别是异常 存在于特定患者的整个转移负担中。这个有指导的研究生涯的目标是 开发建议是描述GIST基因组进展中导致细胞增量的事件的特征 周期失调，特别是影响p16/CDK4/RB1的异常，目的是开发新的 晚期胃肠道间质瘤患者的治疗。利用GIST作为肉瘤中独特的模型进行研究 基因组进展，我的目标1研究解决了细胞周期扰动的假设，包括 P16/CDK4/RB1通路的靶向性异常在晚期GIST中几乎是普遍的事件。这个 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 相结合的方法。这些研究使用全基因组CRISPR筛查来识别合成死亡与 CDK4/6-抑制在GIST中的表达。目的3项研究为联合用药的临床前、体内外验证。 可能增加对CDK4/6抑制的GIST反应的治疗。应聘者的职业目标：加快实现这些目标 翻译研究，我将促进与肉瘤基因组学专家的国际合作， 生物学、病理学、内外科肿瘤学和科学创新。它所包含的研究 职业发展奖将是获得培训、知识和专业知识所需的关键 成功建立独立的翻译肉瘤研究项目并申请终身教职 学术病理学领域的内科医生兼科学家职位。拟议的研究将在 乔纳森·A·弗莱彻博士的指导，他是两个国际GIST研究联盟的领导人，并提供指导 来自一个跨学科的科学咨询委员会，该委员会由肉瘤领域的领先专家组成。 环境：布里格姆妇女医院(BWH)拥有国际公认的研究项目 科学发现培训医生-科学家在翻译研究中的领导作用。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大本营，世界卫生组织 与临床学科有效协作，将科学发现应用于临床实践 改进诊断和治疗。

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.