Tyrosine kinase inhibitors for the treatment of childhood AML

酪氨酸激酶抑制剂用于治疗儿童 AML

基本信息

批准号：
8207924
负责人：
Sharyn D Baker
金额：
$ 33.81万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207924
关键词：
Achievement Acute Myelocytic Leukemia Address Adult Acute Myeloblastic Leukemia Ara-C BAY 54-9085 Benchmarking Biology Blast Cell Cell Line Cell Proliferation Cells Child Childhood Childhood Acute Myeloid Leukemia Clinical Clinical Pharmacology Clinical Trials Cytarabine Disease remission Dose Drug Combinations Drug Exposure Drug Kinetics Evaluation Feedback Future Goals High Dose Chemotherapy Human Induction of Apoptosis Inhibition of Cell Proliferation Knock-out Lead Lesion Mediating Modeling Molecular Mus New Agents Oncogenic Outcome Pharmacodynamics Physiological Processes Play Process Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Refractory Regimen Relapse Research Design Research Project Grants Role Sampling Signal Transduction Survival Rate Therapeutic Translating Transplantation Treatment Protocols Tyrosine Kinase Inhibitor Work Xenograft Model abstracting base conventional therapy cytotoxic cytotoxicity effective therapy experience improved in vitro activity in vivo inhibitor/antagonist novel nucleoside analog pre-clinical success uptake

项目摘要

Abstract 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.

抽象的尽管大于80％的急性粒细胞性白血病（AML）的儿童完成使用高剂量化学疗法或移植的缓解，长期生存率为约50％。没有预期仅常规疗法。因此，新颖的代理和研究设计，其中添加了新代理需要常规疗法。受体酪氨酸激酶在正常中起重要作用生理过程和控制基本细胞活性，包括细胞增殖，分化和生存。对AML生物学的越来越多的理解已牵涉到在白血病过程中，异常的酪氨酸激酶激活。因此，有很大的成人AML对靶向致癌酪氨酸激酶信号传导的新型疗法的热情。我们的中心假设是酪氨酸激酶抑制剂（TKI）将有效治疗童年AML。由于Cytarabine（ARA-C）是治疗AML的最有效药物之一因此包括在每种现代AML治疗方案中用基于细胞丁滨的方案给药。 AML中的新代理不得干扰细胞 ARA-C和细胞毒性活性的吸收和保留。在当前的建议中，我们概述了三组相关研究将解决临床前和临床药理学差距，以允许在儿童时期，未来有前途的多次次激酶抑制剂索拉非尼的合理合理融合。（1）到定义索拉非尼的药代动力学和药效学与ARA-C结合在AML的鼠模型中有效体内。（2）确定索拉非尼增强的机制 ARA-C在AML中的积累和抗肿瘤活性。（3）表征药代动力学索拉非尼的（PK）和AML儿童的药效学（PD）接受基于Cytarabine的儿童方案。该研究项目中描述的工作概述了整合索拉非尼和其他新型药物治疗儿童AML，重点是最佳系统性和肿瘤内药物暴露，并最终改善AML儿童的生存。