Tyrosine kinase inhibitors for the treatment of childhood AML

描述(申请人提供)：尽管超过80%的急性髓细胞白血病(AML)儿童在使用大剂量化疗或移植后完全缓解，但长期存活率约为50%。仅靠常规治疗并不能预期长期疗效的进一步显著改善。因此，将需要在常规治疗的基础上添加新药物的新型药物和研究设计。受体酪氨酸激酶在正常的生理过程中起着重要的作用，控制着细胞的基本活动，包括细胞的增殖、分化和存活。随着人们对急性髓系白血病生物学认识的不断深入，酪氨酸激酶的异常激活在白血病的发生过程中起着重要作用。因此，成人急性髓细胞白血病对靶向致癌酪氨酸激酶信号的新疗法有很大的热情。我们的中心假设是酪氨酸激酶抑制剂(TKIs)对儿童AML的治疗是有效的。由于阿糖胞苷(Ara-C)是治疗AML最有效的药物之一，因此被包括在所有现代AML治疗方案中，因此TKI等新型药物将与以阿糖胞苷为基础的方案一起使用。治疗急性髓系白血病的新药物不得干扰细胞对Ara-C的摄取和保留以及细胞毒活性。在目前的提案中，我们概述了三组相关研究，这些研究将解决临床前和临床药理学方面的空白，以允许未来在儿童AML中合理纳入有前景的多激酶抑制剂索拉非尼。(1)明确索拉非尼与体内有效的Ara-C合用在AML小鼠模型中的药代动力学和药效学。(2)探讨索拉非尼增强Ara-C在AML中蓄积和抗肿瘤活性的机制。(3)研究索拉非尼在接受阿糖胞苷方案治疗的AML患儿中的药代动力学和药效学特征。这项研究项目中描述的工作概述了一种将索拉非尼和其他新型药物整合到儿童AML治疗中的战略，重点是最佳的全身和肿瘤内药物暴露，并最终提高AML儿童的存活率。 公共卫生相关性：尽管超过80%的急性髓细胞白血病(AML)儿童在使用大剂量化疗或移植后完全缓解，但长期存活率约为50%。仅靠常规治疗并不能预期长期疗效的进一步显著改善。我们的研究具有直接的人类相关性，因为它们将导致一种新的酪氨酸激酶抑制剂索拉非尼在儿童AML中的合理结合。

DESCRIPTION (provided by applicant): Despite greater than 80% of children with acute myelogenous leukemia (AML) experiencing complete remission with the use of high-dose chemotherapy or transplantation, the long-term survival rate is approximately 50%. Further significant improvements in long-term outcome are not expected with conventional therapy alone. Thus novel agents and study designs in which new agents are added to conventional therapy will be needed. Receptor tyrosine kinases play important roles in normal physiological processes and control fundamental cellular activities including cell proliferation, differentiation, and survival. The increasing understanding of the biology of AML has implicated aberrant tyrosine kinase activation in the leukemogenic process. Thus, there has been substantial enthusiasm in adult AML for novel therapies that target oncogenic tyrosine kinase signaling. Our central hypothesis is that tyrosine kinase inhibitors (TKIs) will be effective for the treatment of childhood AML. Since cytarabine (Ara-C) is one of the most effective agents for the treatment of AML and is therefore included in every modern AML treatment regimen, novel agents such as TKIs will be administered with cytarabine-based regimens. New agents in AML must not interfere with the cellular uptake and retention of Ara-C and cytotoxic activity. In the current proposal, we outline three sets of related studies that will address the gaps in preclinical and clinical pharmacology to allow for the future rational incorporation of a promising multikinase inhibitor, sorafenib, in childhood AML. (1) To define the pharmacokinetics and pharmacodynamics of sorafenib in combination with Ara-C that is effective in vivo in murine models of AML. (2) To identify mechanisms by which sorafenib enhances the accumulation and antitumor activity of Ara-C in AML. (3) To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of sorafenib in children with AML receiving cytarabine-based regimens. The work described in this research project outlines a strategy to integrate sorafenib and other novel agents in the treatment of childhood AML, with an emphasis on optimal systemic and intratumoral drug exposure, and ultimately improve the survival of children with AML. PUBLIC HEALTH RELEVANCE: Despite greater than 80% of children with acute myelogenous leukemia (AML) experiencing complete remission with the use of high-dose chemotherapy or transplantation, the long-term survival rate is approximately 50%. Further significant improvements in long-term outcome are not expected with conventional therapy alone. Our studies are of direct human relevance as they will lead to the rational incorporation of a novel tyrosine kinase inhibitor, sorafenib, in childhood AML.