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：
8042706
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/8042706
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 base conventional therapy cytotoxic cytotoxicity effective therapy experience improved in vitro activity in vivo inhibitor/antagonist novel nucleoside analog pre-clinical public health relevance success uptake

项目摘要

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.

描述（由申请人提供）：尽管超过80％的患有急性骨髓性白血病（AML）的儿童使用高剂量化疗或移植，但长期存活率约为50％。仅凭常规疗法，预计不会进一步改善长期结局。因此，需要新的药物和研究设计，其中将需要将新药物添加到常规治疗中。受体酪氨酸激酶在正常生理过程中起着重要作用，并控制基本细胞活性，包括细胞增殖，分化和生存。对AML的生物学的越来越多地暗示了白血病过程中异常的酪氨酸激酶活化。因此，成人AML对靶向致癌酪氨酸激酶信号传导的新型疗法具有很大的热情。我们的中心假设是酪氨酸激酶抑制剂（TKI）将有效治疗儿童AML。由于Cytarabine（ARA-C）是治疗AML的最有效药物之一，因此被包括在每种现代AML治疗方案中，因此将使用基于细胞丁滨的方案来施用新型TKIS（例如TKIS）。 AML中的新药物不得干扰ARA-C和细胞毒性活性的细胞摄取和保留。在当前的提案中，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的差距，以允许在儿童AML的未来合理地纳入有希望的多次次峰酶抑制剂Sorafenib。（1）定义索拉非尼的药代动力学和药效学与ARA-C结合使用，在AML的鼠模型中，它在体内有效。（2）确定索拉非尼增强ARA-C在AML中的积累和抗肿瘤活性的机制。（3）索拉非尼的药代动力学（PK）和药效动力学（PD）在患有AML接受基于细胞ara滨的方案的儿童中。该研究项目中描述的工作概述了将索拉非尼和其他新型药物整合在儿童AML治疗中的策略，重点是最佳的全身性和肿瘤内药物暴露，并最终提高了AML儿童的生存。公共卫生相关性：尽管超过80％的患有急性骨髓性白血病（AML）的儿童使用高剂量化疗或移植完全缓解，但长期存活率约为50％。仅凭常规疗法，预计不会进一步改善长期结局。我们的研究具有直接的人类相关性，因为它们将导致童年时期AML的新型酪氨酸激酶抑制剂Sorafenib的合理结合。