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: 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
• 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

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.

摘要 尽管超过80%的急性髓细胞白血病（AML）儿童经历完全性白血病， 使用大剂量化疗或移植缓解，长期生存率为 大约50%。预期长期结局不会进一步显著改善， 传统疗法。因此，新的药物和研究设计，其中加入新的药物， 将需要常规治疗。受体酪氨酸激酶在正常人肝组织中起重要作用， 生理过程和控制基本的细胞活动，包括细胞增殖， 分化和生存。随着对AML生物学的了解不断加深， 在白血病发生过程中异常的酪氨酸激酶激活。因此， 成人AML对靶向致癌酪氨酸激酶信号传导的新疗法的热情。我们 中心假设是酪氨酸激酶抑制剂（TKI）将有效治疗 儿童AML阿糖胞苷（Ara-C）是治疗急性髓细胞白血病（AML）最有效的药物之一， 并因此包括在每一个现代AML治疗方案，新的药物，如TKI将被 给予阿糖胞苷为基础的方案。AML中的新药物不得干扰细胞 Ara-C的摄取和保留以及细胞毒活性。在目前的提案中，我们概述了三套 相关研究将解决临床前和临床药理学方面的差距， 一种有前景的多激酶抑制剂索拉非尼在儿童AML中的未来合理结合。(1)到 定义索拉非尼与阿糖胞苷联合的药代动力学和药效学， 在AML的鼠模型中体内有效。(2)为了确定索拉非尼增强 Ara-C在AML中蓄积及抗肿瘤活性。(3)表征药代动力学 (PK)索拉非尼在接受阿糖胞苷为基础的 养生法本研究项目中描述的工作概述了将索拉非尼和 治疗儿童AML的其他新药，重点是最佳的全身和 肿瘤内药物暴露，并最终提高AML儿童的生存率。