ROLE OF mTOR INHIBITORS AND IL7 IN LYMPHOID MALIGNANCIES

mTOR 抑制剂和 IL7 在淋巴恶性肿瘤中的作用

• 批准号: 6826993
• 负责人: VALERIE I BROWN
• 金额: $ 13.87万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826993
• 关键词: B lymphocyte; acute lymphocytic leukemia; antineoplastics; asparaginase; biological signal transduction; clinical research; combination chemotherapy; cytokine receptors; dexamethasone; doxorubicin; drug screening /evaluation; gene expression; genetically modified animals; human tissue; interleukin 7; laboratory mouse; leukemia; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; sirolimus; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career as an independent investigator in Pediatric Oncology. The principal investigator (PI) has completed subspecialty training in Pediatric Hematology/Oncology at Children's Hospital of Philadelphia (CHOP). She plans to expand her scientific acumen and master new techniques related to functional genomics to understand the molecular mechanisms that contribute to leukemia and lymphoma pathogenesis and apply this knowledge to designing novel therapeutics to treat these malignancies. She will be mentored by Dr. Garrett Brodeur and co-mentored by Dr. Stephan Grupp, while conducting research in Dr. Grupp's lab. Dr. Brodeur, Professor of Pediatrics at the University of Pennsylvania School of Medicine (U. Penn) and Chief of Oncology at CHOP, is a recognized leader in signal transduction in pediatric malignancies. Dr. Grupp, an Assistant Professor of Pediatrics at U. Penn and Director of the Stem Cell Lab at CHOP, is an accomplished physician-scientist in normal B cell development and the pathogenesis of precursor- B acute lymphoblastic leukemia (pre-B ALL). An advisory committee composed of her mentor, co-mentor, and three other highly-regarded physician-scientists will provide career and scientific guidance. The research will focus on evaluating mTOR inhibitors and the role of IL-7 signaling in B cell malignancies. Pre-B ALL is the most common pediatric cancer. Overall, the prognosis for ALL in children is excellent, but in patients who are at high risk or experience relapse, treatment is often difficult and prognosis dismal. Newer, targeted agents need to be identified and integrated into the present cytotoxic chemotherapy regimens. mTOR inhibitors, such as rapamycin, RAD001, and CCI-779, are potential novel therapeutics for B cell malignancies. mTOR inhibitors have been shown to inhibit growth of mature B cells and to have antineoplastic properties in preclinical models of solid tumors and of mature B cell lymphomas. Our preliminary data suggest that rapamycin and RAD001 inhibit the growth of B precursor ALL lines in vitro, and that this inhibitory effect is reversed by IL-7. These agents also demonstrate in vivo activity in a murine model of leukemia/lymphoma. We hypothesize that mTOR inhibitors will be effective agents in the treatment of leukemia, and that one of the growth signals inhibited by these drugs will be IL-7 mediated. Thus, we will evaluate the activity of mTOR inhibitors alone and in combination with conventional chemotherapeutics using both in vitro studies and mouse models of leukemia/lymphoma. We will also investigate the role of IL-7- mediated signaling in response to mTOR inhibitors. The results from the experiments described herein have immediate clinical relevance. The Oncology Division at CHOP provides an ideal setting for training physician-scientists, given its commitment to pediatric research and making available the diverse resources at both CHOP and U. Penn campus. This environment is one in which the PI will successfully develop into an independent investigator by the end of this 5 year period.

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展儿科肿瘤学的独立研究者的学术生涯。主要研究者（PI）已在费城儿童医院（CHOP）完成儿科血液学/肿瘤学的亚专业培训。她计划扩大她的科学敏锐性，掌握与功能基因组学相关的新技术，以了解有助于白血病和淋巴瘤发病机制的分子机制，并将这些知识应用于设计治疗这些恶性肿瘤的新疗法。她将由加勒特布罗德博士指导，并由斯蒂芬·格鲁普博士共同指导，同时在格鲁普博士的实验室进行研究。Brodeur博士是宾夕法尼亚大学医学院的儿科教授。Penn）和CHOP肿瘤学主任，是儿科恶性肿瘤信号转导领域公认的领导者。Grupp博士是美国大学的儿科助理教授。Penn和CHOP干细胞实验室主任，是一位在正常B细胞发育和前体B急性淋巴细胞白血病（前B ALL）发病机制方面有成就的医生兼科学家。一个由她的导师、共同导师和其他三位备受尊敬的医生科学家组成的咨询委员会将提供职业和科学指导。 该研究将重点评估mTOR抑制剂和IL-7信号在B细胞恶性肿瘤中的作用。Pre-B ALL是最常见的儿科癌症。总的来说，儿童ALL的预后很好，但在高危或复发的患者中，治疗往往很困难，预后也很差。需要确定新的靶向药物并将其纳入目前的细胞毒性化疗方案。mTOR抑制剂，如雷帕霉素、RAD 001和CCI-779，是B细胞恶性肿瘤的潜在新型治疗剂。mTOR抑制剂已显示抑制成熟B细胞的生长，并在实体瘤和成熟B细胞淋巴瘤的临床前模型中具有抗肿瘤特性。我们的初步数据表明，雷帕霉素和RAD 001抑制B前体ALL细胞系在体外的生长，这种抑制作用被IL-7逆转。这些药剂还在白血病/淋巴瘤的鼠模型中显示出体内活性。我们假设mTOR抑制剂将是治疗白血病的有效药物，并且这些药物抑制的生长信号之一将是IL-7介导的。因此，我们将使用白血病/淋巴瘤的体外研究和小鼠模型来评估mTOR抑制剂单独和与常规化疗剂组合的活性。我们还将研究IL-7介导的信号传导在mTOR抑制剂应答中的作用。本文所述实验的结果具有直接的临床相关性。 CHOP的肿瘤科为培训医生科学家提供了理想的环境，因为它致力于儿科研究，并提供了CHOP和U的各种资源。宾州大学。在这种环境下，PI将在5年期结束时成功发展为独立研究者。