ROLE OF mTOR INHIBITORS AND IL7 IN LYMPHOID MALIGNANCIES

描述(由申请人提供)：这份建议书描述了一项为期5年的培训计划，旨在发展儿科肿瘤学的学术生涯。首席研究员(PI)已在费城儿童医院(CHOP)完成了儿科血液学/肿瘤学的专科培训。她计划扩大她的科学敏锐度，掌握与功能基因组学相关的新技术，以了解白血病和淋巴瘤发病的分子机制，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·布罗迪尔博士指导，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儿科教授和CHOP肿瘤科主任，是公认的儿科恶性肿瘤信号转导领域的领导者。Grupp博士是宾夕法尼亚大学儿科学助理教授和CHOP干细胞实验室主任，在正常B细胞发育和前驱B急性淋巴细胞白血病(Pre-B ALL)的发病机制方面是一位成就卓著的内科科学家。一个由她的导师、共同导师和其他三位备受尊敬的内科科学家组成的顾问委员会将提供职业和科学指导。 这项研究将集中于评估mTOR抑制剂和IL-7信号在B细胞恶性肿瘤中的作用。前BALL是最常见的儿科癌症。总体而言，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，预后很差。需要确定较新的靶向药物，并将其整合到目前的细胞毒化疗方案中。MTOR抑制剂，如雷帕霉素、RAD001和CCI-779，是治疗B细胞恶性肿瘤的潜在新药。MTOR抑制剂已被证明可以抑制成熟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RAD001在体外对B前体细胞的生长均有抑制作用，这种抑制作用可被IL-7逆转。这些药物还在白血病/淋巴瘤的小鼠模型中显示了体内活性。我们假设mTOR抑制剂将是治疗白血病的有效药物，这些药物抑制的生长信号之一将是IL-7介导的。因此，我们将使用体外研究和小鼠白血病/淋巴瘤模型来评估mTOR抑制剂单独使用以及与传统化疗药物联合使用的活性。我们还将研究IL-7介导的信号在mTOR抑制剂反应中的作用。本文描述的实验结果具有直接的临床意义。 CHOP的肿瘤科为培训内科科学家提供了一个理想的环境，因为它致力于儿科研究，并提供CHOP和宾夕法尼亚大学校区的各种资源。在这种环境中，独立调查员将在这5年期末成功地发展成为一名独立调查员。

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.