CLINICAL TRAILS IN MYELOID MALIGANANCIES WITH MOLECULARLY TARGETED THERAPIES

大约30%的急性心肌梗死患者的病理生理与Flt3基因的激活突变有关。内部 串联重复突变与不良预后相关，尤其是在伴有 正常的细胞遗传学。这项申请的前一个资助期的研究表明，激活突变 Flt3基因在白血病细胞系中的非因子依赖性生长并导致致命的骨髓增殖剂 小鼠骨髓移植模型中的综合征。Flt3酪氨酸的药理抑制剂 KK特异性地杀死这种转化的细胞系，并延长带有这种模型肿瘤的小鼠的生存时间。 与制药公司合作并与我们的实验室密切合作 同事们，达纳-法伯癌症研究所的成人白血病项目率先开发出 治疗急性髓系白血病的临床用Flt3抑制剂。我们确定PKC412和MLN518是作为单一耐受的 药物在AML患者中的应用，并在大多数患者中产生外周血白血病原始细胞计数的减少 他的白血病被证明有Flt3突变。然而，使用所有Flt3的体验 到目前为止，抑制剂表明它们作为单一药物的效用将受到限制，部分原因是药理学方面的原因。 但也是由于急性髓系白血病中其他基因军团的相关性。将有必要结合起来 Flt3抑制剂具有增强靶向抑制或干扰关键途径的药物。我们有 领导了两项研究，在这两项研究中，Flt3抑制剂与化疗联合治疗新诊断的 AML。我们建议扩大Flt3抑制剂加化疗(特定目标1)的研究，通过领导 标准化疗+/-PKC412的最终III期研究，并进行辅助研究 确定Flt3耐药的可能机制。与此美国相关的辅助研究。 组间第三阶段试验将包括(特定目标1b)基线Flt3自动磷酸化的影响和 关于结果和(特定目标1c)Flt3突变改变频率的下游信号 与诊断相比，复发的模式。我们将在项目1中与格里芬博士密切合作，他将 评估Flt3抑制剂和其他抑制剂联合应用对人白血病细胞的体外杀伤作用 通路/细胞过程。然后，我们将进行(特定目标2)临床试验，以测试前景 突变的Flt3急性髓系白血病患者的联合治疗。[第一个此类试验，基于#年的临床前试验 项目1将是PKC412和mTOR抑制剂RAD001的第一阶段研究。辅助性研究将 确定这种酪氨酸激酶抑制和下游信号抑制的组合是否可行 可以抑制预期的目标。]基于这个项目和这个项目中的其他项目的临床前发展 我们期待能够为这种类型的患者设计出新的和潜在有效的治疗方法 急性髓系白血病预后不良。

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.