Targeting cell cycle dysregulation in GIST

项目摘要 研究：胃肠道间质瘤（GIST）是最常见的间叶肿瘤之一。 大多数GIST是由KIT或PDGFRA功能获得性突变引发的，因此已经在 微观形式的GIST。在进展为侵袭性疾病的过程中，早期GIST获得典型的 染色体缺失序列，包括使MAX失活的14 q缺失，促进细胞周期 通过p16转录抑制的失调。基因组突变直接导致p16和其他 细胞周期调节剂出现在进展的后续阶段。虽然酪氨酸激酶抑制剂（TKI）治疗 对于晚期GIST，临床反应显著，继发性TKI耐药通常导致致命性疾病 进展，突出了对生物脆弱性，特别是畸变定义的新目标的需要 存在于给定患者的整个转移负荷中。这个指导研究生涯的目标 开发建议是表征GIST基因组进展中导致细胞增殖的事件， 周期失调，特别是影响p16/CDK 4/RB 1的畸变，目的是开发新的 治疗晚期GIST患者。利用GIST作为肉瘤中的独特模型来研究 基因组的进展，我的目标1研究解决的假设，细胞周期扰动，包括 p16/CDK 4/RB 1通路的靶向畸变几乎是晚期GIST的普遍事件。的 目的2研究的动机是我的假设，即GIST对CDK 4/6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物， GIST中的CDK 4/6抑制。Aim 3研究是联合给药的临床前体外和体内验证 可能增加GIST对CDK 4/6抑制反应的治疗。求职者的职业目标：加快这些 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、内科/外科肿瘤学和科学创新。本研究所涵盖的研究 职业发展奖将是至关重要的，以获得所需的培训，知识和专业知识， 成功建立独立转化肉瘤研究项目并申请终身教职 学术病理学中的医生-科学家职位。拟议的研究将在 乔纳森·A博士的指导。弗莱彻，两个国际GIST研究联盟的领导人，指导 来自一个由肉瘤领域的顶尖专家组成的跨学科科学咨询委员会。 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-科学家在转化研究中发挥领导作用。三围 病理学系是肉瘤/GIST诊断，生物学和遗传学领域的全球领导者的所在地， 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。

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.