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

基本信息

批准号：
7475139
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
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7475139
关键词：
Advisory Committees Antineoplastic Agents B lymphoid malignancy B-Cell Development B-Cell Lymphomas B-Lymphocytes Bone Marrow Transplantation CCI-779 Cells Chemotherapy-Oncologic Procedure Child Childhood Class Cytotoxic Chemotherapy Data Dexamethasone/Doxorubicin Environment Exposure to Growth Growth Factor Human Immunoblotting In Vitro Inbred NOD Mice Interleukin 7 Receptor Interleukin-7 Knowledge Leukemic Cell Lymphoblastic Leukemia Malignant Childhood Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Mature B-Lymphocyte Mediating Mentors Microarray Analysis Modeling Molecular Mus Non-Hodgkin&apos s Lymphoma Pathogenesis Patients Pediatric Hematology/Oncology Pediatric Hospitals Pediatric Oncology Pediatric Research Pediatrics Pennsylvania Pharmaceutical Preparations Phase I Clinical Trials Philadelphia Physicians Pilot Projects Pre-B Acute Lymphoblastic Leukemia Pre-Clinical Model Principal Investigator Program Development Property Prophylactic treatment Relapse Research Research Personnel Resources Risk Role Scientist Signal Pathway Signal Transduction Sirolimus Solid Neoplasm Stem cells Techniques Testing Therapeutic Tissue-Specific Gene Expression Training Training Programs Transgenic Mice Universities Xenograft procedure asparaginase base career clinically relevant design experience functional genomics graft vs host disease in vivo inhibitor/antagonist leukemia leukemia/lymphoma mTOR Inhibitor medical schools mouse model novel therapeutics oncology outcome forecast professor research study response therapeutic target

项目摘要

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）：该提案描述了一个为期 5 年的培训计划，旨在作为儿科肿瘤学独立研究者发展学术职业。主要研究者 (PI) 已在费城儿童医院 (CHOP) 完成了儿科血液学/肿瘤学的亚专业培训。她计划扩大自己的科学敏锐度，掌握与功能基因组学相关的新技术，以了解导致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。她将在 Garrett Brodeur 博士的指导下和 Stephan Grupp 博士的共同指导下，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) 儿科教授兼 CHOP 肿瘤科主任，是儿科恶性肿瘤信号转导领域公认的领导者。 Grupp 博士是宾夕法尼亚大学儿科助理教授兼 CHOP 干细胞实验室主任，是一位在正常 B 细胞发育和前体 B 型急性淋巴细胞白血病 (pre-B ALL) 发病机制方面颇有造诣的医师科学家。由她的导师、共同导师和其他三名备受尊敬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。总体而言，儿童 ALL 的预后良好，但对于高危或复发的患者，治疗往往很困难，预后较差。需要识别更新的靶向药物并将其整合到现有的细胞毒性化疗方案中。 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型疗法。 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 在体外抑制 B 前体 ALL 系的生长，并且这种抑制作用可被 IL-7 逆转。这些药物还在白血病/淋巴瘤小鼠模型中表现出体内活性。我们假设 mTOR 抑制剂将成为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，我们将使用体外研究和白血病/淋巴瘤小鼠模型来评估单独使用 mTOR 抑制剂以及与常规化疗药物联合使用的活性。我们还将研究 IL-7 介导的信号传导在 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。鉴于 CHOP 肿瘤科致力于儿科研究并在 CHOP 和宾夕法尼亚大学校园提供多样化资源，因此它为培训医师科学家提供了理想的环境。在这种环境中，PI 将在 5 年期结束时成功发展成为一名独立调查员。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia.

mTOR 抑制剂与甲氨蝶呤具有协同作用：治疗急性淋巴细胞白血病的有效组合。

DOI：
10.1182/blood-2008-02-137141
发表时间：
2008-09-01
期刊：
Blood
影响因子：
20.3
作者：
D. Teachey;C. Sheen;Junior Hall;T. Ryan;V. Brown;J. Fish;G. Reid;A. Seif;R. Norris;Yueh J. Ch
通讯作者：
Yueh J. Ch

Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies.

雷帕霉素抑制剂的哺乳动物靶点及其在白血病和其他血液恶性肿瘤治疗中的潜在作用。

DOI：
发表时间：
2009-06
期刊：
影响因子：
6.5
作者：
Teachey, David T;Grupp, Stephan A;Brown, Valerie I
通讯作者：
Brown, Valerie I

Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies.

针对患有血液系统恶性肿瘤的儿童的 PI3K/AKT/mTOR 信号轴。

DOI：
发表时间：
2012-10-01
期刊：
影响因子：
0
作者：
Barrett, David;Brown, Valerie I;Grupp, Stephan A;Teachey, David T
通讯作者：
Teachey, David T

Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease.

急性淋巴细胞白血病和淋巴增殖性疾病的新分子和细胞治疗靶点。

DOI：
发表时间：
2008
期刊：
影响因子：
4.4
作者：
Brown, Valerie I;Seif, Alix E;Reid, Gregor S D;Teachey, David T;Grupp, Stephan A
通讯作者：
Grupp, Stephan A

Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling.

胸腺基质来源的淋巴细胞生成素可诱导前 B 白血病增殖并拮抗 mTOR 抑制剂，表明白细胞介素 7Rα 信号传导发挥作用。

DOI：
10.1158/0008-5472.can-06-4704
发表时间：
2007-10-15
期刊：
Cancer research
影响因子：
11.2
作者：
V. Brown;Jessica Hulitt;J. Fish;C. Sheen;M. Bruno;Qing Xu;M. Carroll;Junjie Fang;D. Teachey;S. Grupp
通讯作者：
S. Grupp