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

描述（由申请人提供）：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介导c-KIT依赖性癌症对靶向治疗的反应的理解。原癌基因c-KIT通过激活突变在许多人类癌症中失调，这些癌症通常对常规治疗无效。虽然对靶向c-KIT抑制剂（如伊马替尼）的临床反应已经让临床医生非常满意，但对于大多数肿瘤最终遭受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对伊马替尼的反应将扩大我们对基本细胞途径的科学知识，并转化为新的治疗机会。该提案的目的是研究靶向c-KIT抑制对自噬和凋亡的影响，这两个基本的细胞过程调节细胞存活和死亡，以及这两个过程之间的相互作用如何影响c-KIT依赖性癌细胞的存活，死亡和对治疗的反应。具体目标是：1）研究细胞凋亡在c-KIT依赖性癌症对伊马替尼治疗的反应中的重要性，2）研究自噬在c-KIT依赖性癌症对伊马替尼治疗的反应中的重要性，3）研究BIM和FOXO 3a在c-KIT依赖性癌症对靶向治疗的反应中将细胞凋亡和自噬联系起来的作用。这些目标解决了癌细胞生物学的基本问题，并有机会将结果立即转化为治疗c-KIT依赖性癌症的新治疗方法以及潜在的其他靶向癌症疗法。该研究计划是科学，技术，临床和职业发展组成部分的结构化计划的一部分。该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/肿瘤学部门内进行，该部门在培训成功的医生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的临床敏锐度，这也将激励和通知他的实验室研究。该职业发展计划将建立在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研究者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.