USE OF mTOR INHIBITORS IN B CELL LEUKEMIA

mTOR 抑制剂在 B 细胞白血病中的应用

• 批准号: 7230434
• 负责人: STEPHAN A. GRUPP
• 金额: $ 30.85万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230434
• 关键词: Acute Lymphocytic Leukemia; Apoptosis; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Biological; Biological Assay; Blast Cell; Bone Marrow; Bone Marrow Transplantation; CCI-779; Cell Line; Cells; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Class; Clinical; Clinical Trials; Data; Disease; Effectiveness; Follow-Up Studies; Growth; Growth Factor; Human; Immunosuppressive Agents; In Vitro; Inbred NOD Mice; Interleukin-7; Leukemic Cell; Lymphocyte Activation; Malignant Neoplasms; Malignant lymphoid neoplasm; Mature B-Lymphocyte; Modeling; Mus; New Agents; Non-Hodgkin' s Lymphoma; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Pilot Projects; Plants; Prophylactic treatment; Relapse; Resistance; Role; SDZ RAD; STAT3 gene; STAT5A gene; Sampling; Serum; Signal Pathway; Signal Transduction; Sirolimus; Surrogate Markers; TSLP gene; Therapeutic; Transgenic Mice; Translating; Translational Research; Transplantation; Xenograft procedure; base; design; experience; graft vs host disease; human FRAP1 protein; human TSLP protein; in vivo; inhibitor/antagonist; leukemia; leukemia/lymphoma; mTOR Inhibitor; mTOR Signaling Pathway; pilot trial; programs; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Rapamycin, everolimus and CCI-779 are mTOR inhibitors (MTIs). This class of drugs was initially developed for use as an immunosuppressive after transplantation, but these drugs have long been recognized to have antiproliferative effects in cancer. MTIs may also inhibit mature B lymphocyte activation, and may inhibit the growth of mature B cell lymphomas. Precursor-B acute lymphoblastic leukemia is the most common childhood malignancy. Childhood ALL is successfully treated in 70% of patients, but in the 30% of patients who experience relapse, treatment is difficult, outcome uncertain and new agents are needed. Our preliminary data suggest that rapamycin is active in pre-B ALL. Rapamycin inhibits the growth of B precursor ALL lines in vitro, and we have also demonstrated activity in a murine model of leukemia/lymphoma. We hypothesize that MTIs may be effective drugs in the treatment of leukemia, and that one of the growth signals inhibited by these drugs in precursor B cells may be a signaling pathway activated by both IL-7 and TSLP. In order to evaluate MTI in ALL and the role of IL-7Ra signaling in this disease, we propose the following Specific Aims: 1) MTI powerfully inhibit ALL growth and induce apoptosis in ALL cells. We hypothesize that molecules activating IL-7Ra signaling, including TSLP, may be important in ALL growth and modulate the effect of MTI on ALL. We will: (a) Assess the effect of TSLP on ALL cells and the response to MTI; (b) assess the effect of TSLP on JAKs, STAT3, STAT5 and S6K1 in primary human ALL and compare it to the response to IL-7; and (c) use SCID/NOD expansion of primary ALL cells to investigate mTOR pathway targets in primary human ALL. 2) We will utilize SCID/NOD xenograft and stromal culture models to assess the impact of MTI on growth of primary human ALL cells obtained from COG clinical trials and pilot trials of MTI in ALL (aim 3). 3) As part of an overall investigational/translational plan, we will conduct: (a) a phase I trial of rapamycin in children with relapsed leukemia and non-Hodgkin lymphoma; (b) a pilot study of rapamycin as combined relapse/graft vs. host disease prophylaxis after bone marrow transplant for lymphoid malignancies. These trials are a critical part of the overall translational research plan and results from patient serum and biological samples will be used to refine the treatment approach, direct basic mechanistic experiments and design follow-up studies of this class of drugs in lymphoid malignancies. These studies will immediately translate to the designs of follow-up studies of these agents.

描述（由申请人提供）：雷帕霉素、依维莫司和CCI-779是mTOR抑制剂（MTI）。这类药物最初是为了在移植后用作免疫抑制剂而开发的，但这些药物很早就被认为具有抗癌症增殖作用。 MTI 还可能抑制成熟 B 淋巴细胞活化，并可能抑制成熟 B 细胞淋巴瘤的生长。前体-B 急性淋巴细胞白血病是最常见的儿童恶性肿瘤。 70% 的儿童 ALL 患者得到成功治疗，但 30% 的患者复发，治疗很困难，结果不确定，需要新的药物。我们的初步数据表明雷帕霉素在前 B ALL 中具有活性。雷帕霉素在体外抑制 B 前体 ALL 系的生长，我们还在白血病/淋巴瘤小鼠模型中证明了其活性。我们假设 MTI 可能是治疗白血病的有效药物，并且这些药物抑制的前体 B 细胞中的生长信号之一可能是由 IL-7 和 TSLP 激活的信号通路。为了评估 ALL 中的 MTI 以及 IL-7Ra 信号传导在该疾病中的作用，我们提出以下具体目标： 1) MTI 强力抑制 ALL 细胞生长并诱导 ALL 细胞凋亡。我们假设激活 IL-7Ra 信号传导的分子（包括 TSLP）可能在 ALL 生长中发挥重要作用，并调节 MTI 对 ALL 的作用。我们将： (a) 评估 TSLP 对 ALL 细胞的影响以及对 MTI 的反应； (b) 评估 TSLP 对原发性人类 ALL 中的 JAK、STAT3、STAT5 和 S6K1 的影响，并将其与对 IL-7 的反应进行比较； (c) 使用原代 ALL 细胞的 SCID/NOD 扩增来研究原代人类 ALL 中的 mTOR 通路靶标。 2) 我们将利用 SCID/NOD 异种移植和基质培养模型来评估 MTI 对从 COG 临床试验和 MTI 在 ALL 中的试点试验获得的原代人类 ALL 细胞生长的影响（目标 3）。 3) 作为总体研究/转化计划的一部分，我们将进行： (a) 在患有复发性白血病和非霍奇金淋巴瘤的儿童中进行雷帕霉素的 I 期试验； (b) 雷帕霉素作为淋巴恶性肿瘤骨髓移植后复发/移植物抗宿主病联合预防的初步研究。这些试验是整体转化研究计划的关键部分，患者血清和生物样本的结果将用于完善治疗方法、指导基本机制实验并设计此类药物在淋巴恶性肿瘤中的后续研究。这些研究将立即转化为这些药物的后续研究设计。