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: 6952422
• 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/6952422
• 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）：该提案描述了一项为期5年的培训计划，以发展为儿科肿瘤学独立研究者的学术职业。首席研究员（PI）已完成费城儿童医院（CHOP）的小儿血液学/肿瘤学的专科培训。她计划扩大与功能基因组学相关的科学敏锐度和掌握新技术，以了解有助于白血病和淋巴瘤发病机理的分子机制，并将这些知识应用于设计新型疗法以治疗这些恶性肿瘤。她将由Garrett Brodeur博士指导，并由Stephan Grupp博士合作，同时在Grupp博士的实验室进行研究。 Brodeur博士是宾夕法尼亚大学医学院（U. Penn）的儿科教授，CHOP肿瘤学的负责人，是儿科恶性肿瘤信号转导的公认领导者。 Grupp博士是U. Penn的儿科助理教授，CHOP的干细胞实验室主任，是正常B细胞​​发育中的一位出色的医师科学家，并且是前体急性淋巴细胞性白血病（前B均） 。由她的导师，联合学者和其他三位备受瞩目的医师科学家组成的咨询委员会将提供职业和科学指导。 该研究将着重于评估MTOR抑制剂以及IL-7信号在B细胞恶性肿瘤中的作用。 BE-B全部是最常见的小儿癌。总体而言，所有儿童中所有人的预后都很棒，但是对于患有高风险或经验复发的患者，治疗通常很困难且预后令人沮丧。需要鉴定出更新的靶向剂并将其整合到当前的细胞毒性化学疗法方案中。 MTOR抑制剂，例如雷帕霉素，RAD001和CCI-779，是B细胞恶性肿瘤的潜在新型疗法。 MTOR抑制剂已显示可抑制成熟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塑性特性。我们的初步数据表明，雷帕霉素和RAD001抑制了B前体的生长在体外所有线，并且这种抑制作用被IL-7逆转。这些药物在白血病/淋巴瘤的鼠模型中还表现出体内活性。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一种生长信号将是IL-7介导的。因此，我们将使用体外研究和白血病/淋巴瘤的小鼠模型来评估单独使用MTOR抑制剂的活性，并与常规化学治疗剂结合使用。我们还将研究IL-7-介导的信号转导对MTOR抑制剂的作用。本文所述的实验的结果具有直接的临床相关性。 CHOP的肿瘤学部门为培训医师科学家提供了理想的环境，鉴于其致力于儿科研究并为CHOP和U. Penn Campus提供多样化的资源。在这5年结束时，这种环境将成功发展为独立研究者的环境。