Autophagy and apoptosis in the response of c-KIT cancers to targeted therapy

描述(申请人提供)：候选人提出了一个5年的职业发展计划，旨在促进我们对不同细胞存活和死亡机制之间的相互作用如何调节c-kit依赖型癌症对靶向治疗的反应的理解。原癌基因c-kit通过在一些人类癌症中激活突变而失控，这些突变通常对传统疗法难以奏效。虽然对靶向c-kit抑制剂的临床反应，如伊马替尼，已经让临床医生非常满意，但对于大多数肿瘤最终发生致命复发的患者来说，疗效仍然只是一个起点。因此，研究和表征c-kit介导的细胞死亡和存活机制在伊马替尼的反应中将扩大我们对基本细胞通路的科学知识，并转化为新的治疗机会。这项建议的目的是研究靶向抑制c-kit对自噬和凋亡的影响，这是调节细胞生存和死亡的两个基本细胞过程，以及这两个过程之间的相互作用如何影响c-kit依赖的癌细胞的生存、死亡和治疗反应。其具体目的是：1)探讨细胞凋亡在c-kit依赖肿瘤对伊马替尼治疗反应中的重要性；2)探讨自噬在c-kit依赖肿瘤对伊马替尼治疗反应中的重要性；3)探讨BIM和FOXO3a在c-kit依赖肿瘤靶向治疗反应中连接细胞凋亡和自噬的作用。这些目的是解决癌细胞生物学的基本问题，有机会立即将结果转化为治疗c-kit依赖癌症的新治疗方法，以及潜在的其他靶向癌症治疗方法。这项研究提案是科学、技术、临床和职业发展组成部分的结构化计划的一部分。这项研究将在波士顿儿童医院的大卫·威廉姆斯博士的指导下进行，并在波士顿儿童医院/达纳·法伯癌症研究所的儿科血液学/肿瘤科进行，该研究所在培养成功的内科科学家方面有着杰出的记录。此外，候选人将继续在波士顿儿童医院获得儿科肿瘤学方面的临床经验，这也将激励和指导他的实验室研究。这项职业发展计划将建立在这位候选人之前的研究和临床经验的基础上，并确保他继续发展成为一名成功的独立调查员所需的基本专业知识，重点是癌症生物学和临床儿科肿瘤学家。

DESCRIPTION (provided by applicant): The candidate presents a 5-year career development plan that seeks to advance our understanding of how the interaction between different cell survival and death mechanisms mediate the response of c-KIT dependent cancers to targeted therapy. The proto-oncogene c-KIT is dysregulated via activating mutations in a number of human cancers that are generally refractory to conventional therapy. While the clinical responses to targeted c- KIT inhibitors, such as imatinib, have been hugely satisfying to clinicians, for the majority of patients whose tumors have ultimately suffered fatal relapses the efficacy remains only a starting point. Accordingly, investigating and characterizing c-KIT mediated cell death and survival mechanisms in the response to imatinib will expand both our scientific knowledge of basic cellular pathways as well as translate into new therapeutic opportunities. The aim of this proposal is to investigate the effects of targeted c-KIT inhibition on autophagy and apoptosis, two fundamental cellular processes that regulate cell survival and death, and how the interaction between these two processes impacts c-KIT dependent cancer cell survival, death, and response to therapy. The specific aims are: 1) To investigate the importance of apoptosis in the response of c-KIT dependent cancers to imatinib therapy, 2) To investigate the importance of autophagy in the response of c-KIT dependent cancers to imatinib therapy, and 3) To investigate the role of BIM and FOXO3a in connecting apoptosis and autophagy in the response of c-KIT dependent cancers to targeted therapy. These aims address fundamental questions of cancer cell biology with the opportunity to immediately translate the results into new therapeutic approaches in the treatment of c-KIT dependent cancers as well as potentially other targeted cancer therapies. This research proposal is part of a structured plan of scientific, technical, clinical, and career development components. The research will performed under the guidance of Dr. David Williams at Children's Hospital Boston and within the Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute, which has a distinguished record of training successful physician scientists. In addition, the candidate will continue to gain clinical acumen in pediatric oncology at Children's Hospital Boston that will also inspire and inform his laboratory research. This career development plan will build upon this candidate's prior research and clinical experiences and ensure that he continues to develop the essential expertise required to become a successful independent investigator with a focus on cancer biology and clinical pediatric oncologist.