Multiple kinase target inhibition with EMND-2076 in multiple myeloma

描述(由申请人提供)：目前多发性骨髓瘤(MM)的治疗方法仍然不令人满意，尽管最近在治疗方面有所改进，但这种疾病仍然无法治愈，这表明需要继续研究新的药物。我们在MM中研究了一种新的药物ENMD-2076。ENMD-2076是一种口服生物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，我们已经证明ENMD-2076在体外和体内对MM细胞株和原代MM细胞具有显著的活性，并靶向于对骨髓瘤细胞的生长和存活至关重要的多个途径。除了对MM细胞具有细胞毒作用外，我们还发现ENMD-2076可切割Mcl-1，下调抗凋亡蛋白Survivin和X连锁凋亡抑制因子(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以及极光激酶A和B，诱导G2/M期细胞周期停滞；抑制血管生成。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的临床开发提供了强有力的理论基础。目前还没有ENMD-2076的临床经验报道。因此，基于我们的实验室研究，我们建议启动ENMD-2076在MM患者中的临床研究。具体来说，我们建议1)进行I期试验，以研究口服ENMD-2076对复发或难治性MM患者的剂量限制毒性和最大耐受量，2)描述ENMD-2076口服后的药代动力学特征，3)评估ENMD-2076在我们的临床前研究中确定的重要靶向通路上的体内生物活性，并探索其中一些作为潜在生物标志物用于未来临床试验测试的可行性，这些临床试验将评估疗效。本研究结果将对理解ENMD-2076的临床作用机制以及在未来的临床研究中的最佳使用具有重要意义，对这种目前无法治愈的疾病的转归具有重要意义。 公共卫生相关性：多发性骨髓瘤(MM)仍然是一种无法治愈的癌症，目前的治疗方法表明，需要继续研究和开发新药。在我们的实验室里，我们研究了一种新药ENMD-2076，它对MM细胞具有抑制作用。我们已经证明了ENMD-2076可以有效地杀死骨髓瘤细胞，并似乎针对骨髓瘤细胞生长和生存至关重要的一些途径。我们的研究表明ENMD-2076有希望用于多发性骨髓瘤的治疗，应该进行临床研究。目前还没有使用ENMD-2076的重要临床经验。因此，为了开发这种治疗MM的新药物，我们建议进行一项I期试验，以确定ENMD-2076对复发或耐药MM患者的毒性和安全剂量。伴随试验进行的实验室研究，包括测定不同剂量后药物在患者体内的浓度，以及它在患者体内的生物活性，将使我们更好地了解其临床作用机制，以及它在MM中的最佳发展方式。我们提议的试验结果有望最终改善这种疾病的患者的预后。

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.