USE OF mTOR INHIBITORS IN B CELL LEUKEMIA

描述(申请人提供)：雷帕霉素、伊维洛莫斯和CCI-779是mTOR抑制剂(MTI)。这类药物最初被开发用于移植后的免疫抑制，但这些药物长期以来一直被认为在癌症中具有抗增殖作用。MTI还可能抑制成熟B淋巴细胞的激活，并可能抑制成熟B细胞淋巴瘤的生长。前体B急性淋巴细胞性白血病是儿童最常见的恶性肿瘤。70%的儿童ALL患者治疗成功，但在30%复发的患者中，治疗困难，结果不确定，需要新的药物。我们的初步数据表明，雷帕霉素在前B-ALL中是活跃的。雷帕霉素在体外抑制B前体细胞的生长，我们也在白血病/淋巴瘤的小鼠模型中证明了活性。我们推测MTI可能是治疗白血病的有效药物，这些药物抑制前体B细胞生长的信号之一可能是由IL-7和TSLP共同激活的信号通路。为了评估急性淋巴细胞白血病的MTI和IL-7ra信号在该疾病中的作用，我们提出了以下具体目标： 1)MTI能有效抑制ALL细胞的生长并诱导其凋亡。我们推测，激活IL-7ra信号的分子，包括TSLP，可能在所有的生长过程中都很重要，并调节MTI对ALL的影响。我们将：(A)评估TSLP对ALL细胞的影响和对MTI的反应；(B)评估TSLP对原发人ALL中JAKs、STAT3、STAT5和S6K1的影响，并将其与IL-7的反应进行比较；(C)利用原代ALL细胞的SCID/NOD扩增来研究原发人ALL中mTOR通路的靶点。 2)我们将利用SCID/NOD异种移植和基质培养模型来评估MTI对原代人ALL细胞生长的影响，这些细胞来自COG临床试验和MTI在ALL中的初步试验(目标3)。 3)作为总体研究/转化计划的一部分，我们将进行：(A)雷帕霉素在儿童复发性白血病和非霍奇金淋巴瘤中的I期试验；(B)雷帕霉素作为淋巴恶性肿瘤骨髓移植后复发/移植物与宿主疾病联合预防的初步研究。这些试验是整个转化研究计划的关键部分，来自患者血清和生物样本的结果将用于改进治疗方法，指导基本机制实验，并设计这类药物在淋巴系统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的设计。

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.