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

• 批准号: 7787139
• 负责人: Sherif S Farag
• 金额: $ 31.96万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787139
• 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; 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; public health relevance; response; survivin

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. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) remains an incurable cancer with current treatment, indicating the need for continued investigation and development of new drugs. In our laboratory, we have investigated a novel drug, ENMD- 2076, for its activity against MM cells. We have shown that ENMD-2076 potently kills myeloma cells, and appears to target a number of pathways on which the myeloma cells critically depend for their growth and survival. Our studies suggest that ENMD-2076 has promise for the treatment of MM, and that it should undergo clinical investigation. No significant clinical experience with ENMD-2076 exists. Therefore, to develop this novel agent in MM, we propose to conduct a phase I trial to determine the toxicity and safe dose of ENMD- 2076 in patients with relapsed or resistant MM. The laboratory studies that will accompany the trial, including determination of the drug's concentration in blood after different doses, and its biological activity in patients will give better understanding of its clinical mechanism of action and the way it may be best developed in MM. The results of our proposed trial hold promise to eventually improve the outcome of patients with this disease.

描述（由申请人提供）：当前对多发性骨髓瘤（MM）的治疗仍然不令人满意，尽管治疗最近有所改善，但该疾病仍然无法治愈，这表明需要继续研究新型药物。我们已经用MM调查了一种新型代理ENMD-2076。 ENMD-2076是一种口服的可生物利用，多目标激酶抑制剂，具有复杂的作用机理，包括抗磷酸和促凋亡活性以及血管生成的抑制。在临床前研究中，我们已经表明，ENMD-2076具有显着的体外和体内活性对MM细胞系和原代MM细胞，并且靶向对骨髓瘤细胞生长和存活至关重要的多个途径。除了对MM细胞具有细胞毒性外，我们还表明，ENMD-2076裂解MCL-1及向下调节抗凋亡蛋白的抗凋亡蛋白存活和X-C-连接凋亡抑制剂（XIAP）。抑制磷脂酰肌醇3-激酶（PI3K）/AKT途径，成纤维细胞生长因子受体-3（FGFR3）受体酪氨酸激酶活性和Aurora激酶A和B，在G2/m相细胞中诱导循环循环；并抑制血管生成。针对MM细胞的显着活性以及该药物在MM发病机理中靶向的途径的重要性为ENMD-2076在MM中的临床发育提供了强大的基本原理。 ENMD-2076尚无临床经验。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。 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在将来评估功效的未来临床试验中，利用其中一些作为测试的潜在生物标志物的可行性。这项研究的结果对于理解ENMD-2076作用机理及其在MM的未来临床研究中的最佳用途至关重要，这对于当前无法治愈的疾病的结果具有重要意义。 公共卫生相关性：多发性骨髓瘤（MM）仍然是无法治愈的癌症，目前治疗表明需要继续研究和开发新药。在我们的实验室中，我们研究了一种新型药物ENMD-2076，其活性对MM细胞。我们已经表明，ENMD-2076有效地杀死了骨髓瘤细胞，并且似乎针对多个骨髓瘤细胞的途径，这些途径严重取决于其生长和生存。我们的研究表明，ENMD-2076有望治疗MM，并且应该接受临床研究。 ENMD-2076没有大量的临床经验。因此，为了在MM中开发这种新颖的药物，我们建议进行I期试验，以确定ENMD-2076的毒性和安全剂量对复发或抗性MM的患者。该试验将伴随的实验室研究，包括确定药物在不同剂量后的血液中的浓度，以及其在患者中的生物学活性将更好地了解其临床作用机理以及在MM中最好开发的方法。我们拟议的试验结果持希望最终改善该疾病患者的结果。