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，特别是在细胞遗传学正常的亚组中。本申请先前资助期的工作表明，FLT 3的激活突变在白血病细胞系中赋予因子非依赖性生长，并在小鼠骨髓移植模型中导致致命的骨髓增殖综合征。FLT 3酪氨酸激酶的药理学抑制剂特异性地杀死这种转化细胞系并延长具有这种模型肿瘤的小鼠的存活。 通过与制药公司的合作以及与我们实验室同事的密切合作，Dana-Farber癌症研究所的成人白血病项目率先开发了用于AML临床的FLT 3抑制剂。我们确定，PKC 412和MLN 518作为单药在AML患者中耐受，并且在大多数白血病被记录为具有FLT 3突变的患者中产生外周白血病原始细胞计数减少。然而，迄今为止所有FLT 3抑制剂的经验表明，它们作为单一药物的效用将是有限的，部分原因是药理学方面的考虑，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抑制剂与增强靶抑制或干扰关键途径的药物联合使用。我们已经领导了两项研究，其中FLT 3抑制剂与新诊断的AML患者的化疗相结合。我们建议通过领导标准化疗+/-PKC 412的确定性III期研究来扩展FLT 3抑制剂加化疗的研究（具体目标1），并进行辅助研究以确定FLT 3耐药的潜在机制。与这项美国组间III期试验相关的辅助研究将包括（特定目标1b）基线FLT 3自磷酸化和下游信号传导对结果的影响，以及（特定目标1c）与诊断相比，复发时FLT 3突变模式的变化频率。我们将与项目1中的Griffin博士密切合作，Griffin博士将评估FLT 3抑制剂和其他途径/细胞过程抑制剂组合对体外人白血病细胞的杀伤作用。然后，我们将进行（具体目标2）临床试验，以在突变型FLT 3 AML患者中测试有希望的组合。[The基于项目1中的临床前实验，第一个这样的试验将是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并且可以抑制预期的靶标。基于本项目和本项目中的其他项目的临床前开发， 我们期望能够为这种预后不良的AML患者设计新的和潜在有效的治疗方法。

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.