Multiple kinase target inhibition with EMND-2076 in multiple myeloma

EMND-2076 对多发性骨髓瘤的多激酶靶点抑制

基本信息

批准号：
8013948
负责人：
Sherif S Farag
金额：
$ 31万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2010-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013948
关键词：
1-Phosphatidylinositol 3-Kinase Aftercare Alkylating Agents Angiogenesis Inhibition Angiopoietin-1 Apoptotic Area Under Curve Bioavailable Biological Biological Assay Biological Markers Biopsy Specimen Blood Bone Marrow Bortezomib Cell Cycle Arrest Cell Line Cells Cleaved cell Clinical Clinical Trials Complex Core Biopsy Critical Pathways Cytotoxic agent Data Development Disease Dose Dose-Limiting Down-Regulation Drug Kinetics Drug resistance Enzyme-Linked Immunosorbent Assay Fibroblast Growth Factor 2 Future Growth Half-Life Health Hematopoietic stem cells Histones Immunofluorescence Microscopy In Vitro In complete remission Investigation Laboratories Laboratory Study Malignant Neoplasms Maximum Tolerated Dose Measurement Mitosis Multiple Myeloma Oral Oral Administration Outcome Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Phosphorylation Inhibition Phosphotransferases Plasma Proteins Receptor Inhibition Receptor Protein-Tyrosine Kinases Refractory Relapse Reporting Research Resistance Survival Rate Testing Thalidomide Time Tissues Toxic effect Vascular Endothelial Growth Factors angiogenesis angiogenin aurora kinase aurora-A kinase base conventional therapy cytokine cytotoxic density experience fibroblast growth factor receptor 3 human BIRC4 protein improved in vivo killings kinase inhibitor lenalidomide novel pre-clinical preclinical study response survivin

项目摘要

DESCRIPTION (provided by applicant): Current therapy for multiple Myeloma (MM) remains unsatisfactory, and despite recent improvements in treatment, the disease remains incurable indicating the need for continued investigation of novel agents. We have investigated a novel agent, ENMD-2076, in MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with a complex mechanism of action, including antiproliferative and pro-apoptotic activity, and inhibition of angiogenesis. In preclinical studies, we have shown that ENMD-2076 has significant in vitro and in vivo activity against MM cell lines and primary MM cells, and targets multiple pathways critical to the growth and survival of myeloma cells. In addition to being cytotoxic to MM cells, we have shown that ENMD-2076 cleaves Mcl-1 and down regulates the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis (XIAP); inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, fibroblast growth factor receptor-3 (FGFR3) receptor tyrosine kinase activity, and the aurora kinases A and B, inducing cycle arrest in the G2/M phase cell; and inhibits of angiogenesis. The significant activity against MM cells, and the importance of the pathways targeted by this agent in the pathogenesis of MM, provides strong rationale for clinical development of ENMD- 2076 in MM. No clinical experience has been reported with ENMD-2076. Therefore, based on our laboratory studies we propose to initiate clinical investigation of ENMD-2076 in patients with MM. Specifically, we propose 1) to conduct a phase I trial to investigate the dose limiting toxicity and maximal tolerated dose of oral ENMD-2076 in patients with relapsed or refractory MM, 2) Describe the pharmacokinetic profile of ENMD-2076 following oral administration, and 3) Assess the in vivo biological activity of ENMD-2076 on important target pathways identified in our preclinical studies, and explore the feasibility of utilizing some of these as potential biomarkers for testing in future clinical trials that will assess efficacy. The results of this research will be important to the understanding of clinical mechanism of action of ENMD-2076 and its optimal use in future clinical investigation in MM, which has important significance for the outcome of this currently incurable disease.

描述（由申请人提供）：目前多发性骨髓瘤（MM）的治疗仍然不能令人满意，尽管最近治疗有所改善，但该疾病仍然无法治愈，表明需要继续研究新药。我们在 MM 中研究了一种新药物 ENMD-2076。 ENMD-2076 是一种口服生物可利用的多靶点激酶抑制剂，具有复杂的作用机制，包括抗增殖和促凋亡活性以及抑制血管生成。在临床前研究中，我们表明 ENMD-2076 对 MM 细胞系和原代 MM 细胞具有显着的体外和体内活性，并靶向对骨髓瘤细胞生长和存活至关重要的多种途径。除了对 MM 细胞具有细胞毒性外，我们还发现 ENMD-2076 可以裂解 Mcl-1 并下调抗凋亡蛋白 survivin 和 X 连锁凋亡抑制剂 (XIAP)；抑制磷脂酰肌醇 3 激酶 (PI3K)/Akt 通路、成纤维细胞生长因子受体 3 (FGFR3) 受体酪氨酸激酶活性以及极光激酶 A 和 B，诱导 G2/M 期细胞周期停滞；并抑制血管生成。针对 MM 细胞的显着活性，以及该药物针对的途径在 MM 发病机制中的重要性，为 ENMD-2076 在 MM 中的临床开发提供了强有力的理由。尚未报告 ENMD-2076 的临床经验。因此，根据我们的实验室研究，我们建议在 MM 患者中启动 ENMD-2076 的临床研究。具体来说，我们建议 1) 进行一项 I 期试验，以研究口服 ENMD-2076 在复发或难治性 MM 患者中的剂量限制毒性和最大耐受剂量，2) 描述口服给药后 ENMD-2076 的药代动力学特征，以及3) 评估ENMD-2076对我们临床前研究中确定的重要靶标途径的体内生物活性，并探索利用其中一些作为潜在生物标志物的可行性用于在未来评估疗效的临床试验中进行测试。这项研究的结果对于了解 ENMD-2076 的临床作用机制及其在未来 MM 临床研究中的最佳使用具有重要意义，这对于这种目前无法治愈的疾病的结果具有重要意义。