Tyrosine kinase inhibitors for the treatment of childhood AML

 描述（由申请人提供）：急性髓性白血病（AML）儿童的总生存率已提高到60- 70%。然而，疾病复发后，长期生存的可能性很差（20-30%）。儿童AML的几种亚型具有高复发风险，包括受体酪氨酸激酶FLT 3中具有内部串联重复（ITD）突变的一组。新诊断的FLT 3-ITD阳性AML儿童在接受诱导治疗后接受3-4个疗程的化疗时，总生存率为40%，而FLT 3-ITD突变AML成人的生存率更低。FLT 3-ITD突变发生在约15%的儿童AML和超过30%的成人AML中。FLT 3-ITD阳性AML患者的长期生存率预计不会进一步显著改善，仅使用常规化疗，需要新的治疗策略。在本提案中，我们概述了三个相关项目，以规避和治疗耐药FLT 3-ITD阳性AML，包括：（目的1）确定索拉非尼与克瑞拉尼组合对复发性/难治性儿科FLT 3-ITD+ AML中的药物功效、毒性、PK、PD和抗性特征的影响，我们假设需要最佳FLT 3抑制来抑制TKI耐药继发性TKD突变的出现;（目的2）确定Tec激酶BMX在索拉非尼抗性中的作用，我们假设在FLT 3抑制期间，BMX上调和活化提供了赋予索拉非尼抗性的补偿信号传导途径;和（目的3）鉴定FLT 3-ITD+ AML中有效的索拉非尼组合。在后一个目的中，将评估伊克替尼（一种主要BMX抑制剂）与索拉非尼联合给药时的翻译潜力，我们假设伊克替尼将在索拉非尼治疗期间抑制BMX活性，联合给药将是FLT 3-ITD+ AML的有效治疗策略。我们的策略代表了实验室体外和体内实验方法与临床观察之间的持续相互作用，我们假设这种方法将导致识别重要的，以前未被识别的TKI耐药机制，以及未来发现儿童AML的新治疗策略，改善结局。

 DESCRIPTION (provided by applicant): Overall survival in children with acute myeloid leukemia (AML) has improved to 60-70%. However, after disease recurrence, the likelihood of long-term survival is poor (20-30%). Several subtypes of childhood AML are at high risk of relapse including a group with internal tandem duplication (ITD) mutations in the receptor tyrosine kinase FLT3. Children with newly diagnosed FLT3-ITD-postive AML have an overall survival of 40% when treated with induction therapy followed by 3-4 courses of chemotherapy, whereas worse survival rates have been reported in adults with FLT3-ITD mutated AML. FLT3-ITD mutations occur in about 15% of pediatric AML and more than 30% of adult AML. Further significant improvements in long-term survival of FLT3-ITD-positive AML are not expected with conventional chemotherapy alone and new therapeutic strategies are needed. In this proposal, we outline three related projects to circumvent and treat drug-resistant FLT3-ITD- positive AML including: (Aim 1) to determine the effects of sorafenib in combination with crenolanib on drug efficacy, toxicity, PK, PD and resistance profiles in relapsed/refractory pediatric FLT3-ITD+ AML, with our hypothesis that optimal FLT3 inhibition is required to suppress the emergence of TKI-resistant secondary TKD mutations; (Aim 2) to determine the role of the Tec kinase BMX in sorafenib resistance, with our hypothesis that during FLT3 inhibition, BMX upregulation and activation provides a compensatory signaling pathway that confers resistance to sorafenib; and (Aim 3) to identify effective sorafenib combinations in FLT3-ITD+ AML. In the latter Aim, the translational potential of ibrutinib, a lead BMX inhibitor, when given in combination with sorafenib, will be evaluated, with our hypothesis that ibrutinib will suppress BMX activity during sorafenib treatment and in combination will be an effective treatment strategy for FLT3-ITD+ AML. Our strategy represents a continuous interplay between laboratory in vitro and in vivo experimental approaches and clinical observations, and we hypothesize that this approach will lead to the identification of important, previously unrecognized mechanisms of TKI resistance as well as to the future discovery of novel treatment strategies for childhood AML with improved outcome.