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）：目前多发性骨髓瘤（MM）的治疗仍然不令人满意，尽管最近治疗有所改善，但该疾病仍然无法治愈，这表明需要继续研究新型药物。我们已经研究了一种新的药物，ENMD-2076，在MM。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，并抑制血管生成。在临床前研究中，我们已经证明ENMD-2076对MM细胞系和原代MM细胞具有显著的体外和体内活性，并靶向对骨髓瘤细胞的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，我们已经表明ENMD-2076切割Mcl-1并下调抗凋亡蛋白生存素和X连锁凋亡抑制剂（XIAP）;抑制磷脂酰肌醇3-激酶（PI 3 K）/Akt途径、成纤维细胞生长因子受体-3（FGFR 3）受体酪氨酸激酶活性和极光激酶A和B，诱导G2/M期细胞的周期停滞;并抑制血管生成。针对MM细胞的显著活性以及该药物靶向的通路在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。尚未报道ENMD-2076的临床经验。因此，基于我们的实验室研究，我们建议在MM患者中开始ENMD-2076的临床研究。具体地，我们建议1）进行I期试验以研究复发性或难治性MM患者中口服ENMD-2076的剂量限制性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，和3）评估ENMD-2076对我们临床前研究中鉴定的重要靶向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用于在未来评估功效的临床试验中进行测试的可行性。本研究的结果对于了解ENMD-2076的临床作用机制及其在MM未来临床研究中的最佳使用非常重要，这对这种目前无法治愈的疾病的结局具有重要意义。 公共卫生相关性：多发性骨髓瘤（MM）仍然是目前治疗无法治愈的癌症，这表明需要继续研究和开发新药。在我们的实验室中，我们研究了一种新药ENMD- 2076对MM细胞的活性。我们已经证明，ENMD-2076有效地杀死骨髓瘤细胞，并且似乎靶向骨髓瘤细胞生长和存活所依赖的许多途径。我们的研究表明，ENMD-2076有希望治疗MM，并应进行临床研究。ENMD-2076无显著临床经验。因此，为了在MM中开发这种新药，我们建议进行I期试验，以确定ENMD- 2076在复发或耐药MM患者中的毒性和安全剂量。将伴随试验的实验室研究，包括确定不同剂量后药物在血液中的浓度，它在患者中的生物活性将使人们更好地了解它的临床作用机制，以及它在MM中的最佳开发方式。改善这种疾病患者的预后。