Tyrosine kinase inhibitors for the treatment of childhood AML

 描述(由申请人提供)：儿童急性髓系白血病(AML)的总存活率已提高到60%-70%。然而，在疾病复发后，长期存活的可能性很低(20%-30%)。儿童AML的几种亚型复发的风险很高，包括受体酪氨酸激酶Flt3的内部串联重复(ITD)突变组。新诊断为Flt3-ITD阳性AML的儿童在接受诱导治疗后再接受3-4个疗程的化疗，总存活率为40%，而据报道，患有Flt3-ITD突变的AML的成人存活率较低。大约15%的儿童AML和30%以上的成人AML会发生Flt3-ITD突变。仅用常规化疗不能进一步显着改善Flt3-ITD阳性AML的长期存活率，需要新的治疗策略。在这项建议中，我们概述了避免和治疗耐药的Flt3-ITD阳性AML的三个相关项目，包括：(目的1)确定索拉非尼联合crenolanib对复发/难治性儿童Flt3-ITD+AML的疗效、毒性、PK、PD和耐药性的影响，我们的假设是，需要最佳的Flt3抑制来抑制TKI耐药的继发性TKD突变的出现；(目的2)确定Tec激酶BMX在索拉非尼耐药中的作用，我们的假设是，在Flt3抑制期间，BMX上调和激活提供了一条补偿信号通路，从而提供了对索拉非尼的耐药性；目的3)确定Flt3-ITD+AML中有效的索拉非尼组合。在后一个目标中，我们将评估先导BMX抑制剂ibrutinib与索拉非尼联合应用时的翻译潜力，我们的假设是，ibrutinib将在索拉非尼治疗期间抑制BMX活性，联合使用将是治疗Flt3-ITD+AML的有效策略。我们的策略代表了实验室体外和体内实验方法以及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、以前未被认识的TKI耐药机制，以及未来发现儿童AML的新治疗策略，并改善结果。

 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.