CLINICAL TRAILS IN MYELOID MALIGANANCIES WITH MOLECULARLY TARGETED THERAPIES

FLT 3的激活突变导致大约30%的AMI病例的病理生理学。内部 串联重复突变与不良预后相关，特别是在以下亚组中： 正常的细胞遗传学这项申请的前期资助工作表明，激活突变 FLT 3的表达在白血病细胞系中赋予因子非依赖性生长，并导致致命的骨髓增殖性白血病。 综合征的小鼠骨髓移植模型。FLT 3酪氨酸的药理学抑制剂 激酶特异性地杀死这种转化的细胞系并延长具有这种模型肿瘤的小鼠的存活。 与制药公司合作，并与我们的实验室密切合作， 丹娜-法伯癌症研究所的成人白血病项目已经率先开发了 FLT 3抑制剂在AML中的临床应用。我们确定PKC 412和MLN 518作为单一的治疗剂耐受。 在AML患者中使用药物，并在大多数患者中减少外周白血病原始细胞计数 他的白血病被证实有FLT 3突变然而，所有FLT 3的经验 迄今为止的抑制剂表明，它们作为单一药剂的效用将受到限制，部分原因是药理学上的原因。 这不仅是考虑因素，也是由于AML中其他遗传军团的相关性。有必要将联合收割机 FLT 3抑制剂与增强靶点抑制或干扰关键途径的药物。我们有 领导了两项研究，其中FLT 3抑制剂与化疗相结合，用于新诊断的 急性髓细胞白血病我们建议通过以下方式扩展FLT 3抑制剂联合化疗（特定目标1）的研究： 标准化疗+/-PKC 412的确定性III期研究，并进行辅助研究， 确定FLT 3抗性的潜在机制。与此相关的研究美国 组间III期试验将包括（具体目标1b）基线FLT 3自磷酸化的影响， 下游信号传导对结果和（特异性目的1c）FLT 3突变的变化频率的影响 与诊断相比，复发的模式。我们将与项目1中的格里芬博士密切合作， 评估FLT 3抑制剂和其他抑制剂的组合体外杀伤人白血病细胞 途径/细胞过程。然后，我们将进行（具体目标2）临床试验，以测试有希望的 在突变型FLT 3 AML患者中的联合治疗。[The第一个这样的试验，基于临床前实验， 项目1将是PKC 412和mTOR抑制剂RAD 001的I期研究。辅助研究将 确定酪氨酸激酶抑制与下游信号传导抑制的这种组合是否可行， 可以抑制预期的目标。基于本项目和本项目中的其他项目的临床前开发， 我们希望能够为这种类型的患者设计新的和潜在的有效疗法。 预后不良的AML。

Activation mutations of FLT3 contribute to the pathophysiology of approximately 30% of AMI cases. Internal tandem duplication mutations are associated with an adverse prognosis especially in the subgroup with normal cytogenetics. Work from the prior funding period of this application showed that activating mutations of FLT3 confer factor-independent growth in leukemic cell lines and lead to a fatal myeloproliferative syndrome in a murine bone marrow transplant model. Pharmacological inhibitors of the FLT3 tyrosine kinase specifically kill such transformed cell lines and prolong the survival of mice with this model neoplasm. In partnership with pharmaceutical companies and in close collaboration with our laboratory-based colleagues, the adult leukemia program at the Dana-Farber Cancer Institute has taken the lead in developing FLT3 inhibitors for clinical use in AML. We established that PKC412 and MLN518 were tolerated as single agents in patients with AML and produced a reduction in peripheral leukemic blast count in most patients whose leukemia was documented to have a FLT3 mutation. However, the experience with all the FLT3 inhibitors to date suggests that their utility as single agents will be limited, due in part to pharmacological considerations but also due to the relevance of other genetic legions in AML. It will be necessary to combine FLT3 inhibitors with agents which either enhance target inhibition or interfere with critical pathways. We have led two studies in which a FLT3 inhibitor is combined with chemotherapy in patients with newly diagnosed AML. We propose to extend the studies with FLT3 inhibitors plus chemotherapy (specific Aim 1) by leading a definitive phase III study of standard chemotherapy +/- PKC412 and to perform ancillary studies to determine the potential mechanisms of FLT3 resistance. Ancillary studies associated with this U.S. Intergroup phase III trial will include (Specific Aim 1b) the impact of baseline FLT3 autophosphorylation and downstream signaling on outcome and (Specific Aim 1c) the frequency of changes in FLT3 mutational patterns at relapse compared with diagnosis. We will work closely with Dr. Griffin in Project 1 who will assess killing of human leukemic cells in vitro by combinations of FLT3 inhibitors and inhibitors of other pathways/cellular processes. We will then perform (Specific aim 2) clinical trials to test promising combinations in patients with mutant FLT3 AML. [The first such trial, based on preclinical experiments in Project 1, will be a phase I study of PKC412 and the mTOR inhibitor RAD001. Ancillary studies will determine if this combination of tyrosine kinase inhibition with downstream signaling inhibition is feasible and can inhibit the expected targets.] Based on pre-clinical development in this and the other projects in this grant we anticipate being able to devise new and potentially effective therapies for patients with this type of poor prognosis AML.