Autophagy and Apoptosis in the Response of c-KIT Cancers to Targeted Therapy

c-KIT 癌症对靶向治疗的反应中的自噬和凋亡

• 批准号: 8913061
• 负责人: PETER M GORDON
• 金额: $ 14.34万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913061
• 关键词: Acute Myelocytic Leukemia; Address; Adverse effects; Apoptosis; Apoptotic; Autophagocytosis; BCL2L11 gene; Biological Models; Boston; Cancer Biology; Cancer Patient; Cancer cell line; Caring; Cell Death; Cell Survival; Cell physiology; Cellular biology; Cessation of life; Clinic; Clinical; Complex; Cytotoxic Chemotherapy; Dana-Farber Cancer Institute; Data; Development; Development Plans; Ensure; Failure; Gastrointestinal Stromal Tumors; Germ cell tumor; Human; Imatinib; Individual; Knowledge; Laboratories; Laboratory Research; Link; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Molecular; Mutation; Neuroblastoma; Outcome; Pathway interactions; Patients; Pediatric Hematology; Pediatric Hospitals; Pediatric Oncologist; Pediatric Oncology; Physicians; Process; Proteins; Proto-Oncogenes; Receptor Tyrosine Kinase Gene; Refractory; Regulation; Relapse; Research; Research Personnel; Research Proposals; Role; Scientist; Structure; Training; Translating; Tumor Cell Line; autocrine; cancer cell; cancer therapy; career development; conventional therapy; experience; improved; inhibitor/antagonist; lung small cell carcinoma; mastocytosis; melanoma; novel therapeutic intervention; novel therapeutics; oncology; pediatric patients; research study; response; success; targeted cancer therapy; targeted treatment; therapeutic effectiveness; tumor; tumor progression

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.

描述（由申请人提供）：候选人提出了一项为期5年的职业发展计划，旨在促进我们对不同细胞存活与死亡机制之间相互作用如何介导C-KIT依赖性癌症对靶向治疗的反应的理解。原始癌基因C-KIT通过在许多人类癌症中的激活突变而失调，这些突变通常对常规治疗难治性。虽然诸如伊马替尼等靶向c抑制剂的临床反应对临床医生非常满意，但对于大多数肿瘤最终遭受致命复发的患者而言，疗效仍然只是起点。因此，研究和表征对伊马替尼反应中C-KIT介导的细胞死亡和生存机制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有针对性的C-KIT抑制对自噬和凋亡的影响，这是调节细胞存活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依赖性癌细胞的存活，死亡，死亡，死亡以及对治疗的反应。具体目的是：1）研究凋亡在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，以及3）研究BIM和FOXO3A对依赖性apoptosis和Autoptoper cancit can can-can-can-can-can-can-can-can-can-can can can-can-can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can can的含量的影响。这些目的解决了癌细胞生物学的基本问题，有机会将结果立即转化为治疗C-KIT依赖性癌症以及潜在的其他靶向癌症疗法的新治疗方法。该研究建议是科学，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戴维·威廉姆斯博士的指导下以及波士顿儿童医院/达娜·法伯癌症研究所的儿科血液学/肿瘤科的指导下进行，该研究有培训成功的医师科学家的杰出记录。此外，候选人将继续在波士顿儿童医院获得小儿肿瘤学的临床敏锐度，这也将激发他的实验室研究。这项职业发展计划将基于该候选人的先前研究和临床经验，并确保他继续发展成为成功的独立研究者所需的基本专业知识，专注于癌症生物学和临床小儿肿瘤学家。