USE OF mTOR INHIBITORS IN B CELL LEUKEMIA

描述（由申请人提供）：雷帕霉素、依维莫司和CCI-779是mTOR抑制剂（MTIs）。这类药物最初是作为移植后的免疫抑制剂而开发的，但这些药物长期以来被认为在癌症中具有抗增殖作用。MTIs还可能抑制成熟B淋巴细胞的活化，并可能抑制成熟B细胞淋巴瘤的生长。前体b型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患者成功治疗，但30%复发的患者治疗困难，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b前ALL中有活性。雷帕霉素在体外抑制B前体ALL细胞系的生长，我们也在白血病/淋巴瘤小鼠模型中证明了其活性。我们推测MTIs可能是治疗白血病的有效药物，这些药物抑制前体B细胞中的一个生长信号可能是由IL-7和TSLP激活的信号通路。为了评估MTI在ALL中的作用以及IL-7Ra信号在该疾病中的作用，我们提出以下具体目标：

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.