Tyrosine kinase inhibitors for the treatment of childhood AML

酪氨酸激酶抑制剂用于治疗儿童 AML

• 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
• 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

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%的急性髓性白血病（AML）儿童在使用大剂量化疗或移植后完全缓解，但长期生存率约为50%。单独使用常规治疗预计不会进一步显著改善长期结局。因此，将需要新的药物和研究设计，其中新的药物被添加到常规治疗中。受体酪氨酸激酶在正常生理过程中起重要作用，并控制基本的细胞活动，包括细胞增殖、分化和存活。随着对AML生物学的了解不断增加，发现白血病发生过程中存在异常酪氨酸激酶激活。因此，成人AML患者对靶向致癌酪氨酸激酶信号传导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（TKI）将有效治疗儿童AML。由于阿糖胞苷（Ara-C）是治疗AML最有效的药物之一，因此被纳入每种现代AML治疗方案中，因此新型药物（如TKI）将与基于阿糖胞苷的方案一起给药。AML中的新药物不得干扰细胞对Ara-C的摄取和保留以及细胞毒性活性。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差距，以便将来合理地将一种有前途的多激酶抑制剂索拉非尼纳入儿童AML。(1)确定索拉非尼联合Ara-C在AML小鼠模型中的体内有效药代动力学和药效学。(2)确定索拉非尼增强Ara-C在AML中蓄积和抗肿瘤活性的机制。(3)描述索拉非尼在接受基于阿糖胞苷方案的AML儿童中的药代动力学（PK）和药效学（PD）。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用于治疗儿童AML的策略，重点是最佳的全身和肿瘤内药物暴露，并最终改善AML儿童的生存率。 公共卫生关系：尽管超过80%的急性髓性白血病（AML）儿童在使用大剂量化疗或移植后完全缓解，但长期生存率约为50%。单独使用常规治疗预计不会进一步显著改善长期结局。我们的研究与人类直接相关，因为它们将导致一种新型酪氨酸激酶抑制剂索拉非尼在儿童AML中的合理掺入。