Preclinical Efficacy of Epoxomicin in Multiple Myeloma

描述（由申请人提供）：本提案的目的是确定环氧霉素作为治疗多发性骨髓瘤的潜在疗法的有效性和安全性，多发性骨髓瘤是一种无法治愈的肿瘤，影响70，000名美国人，每年新增15，000例病例，占癌症相关死亡的1-2%。它是一致致命的，80%的患者患有破坏性和进行性骨破坏。确诊后的平均寿命不到三年，这在过去30年里没有明显变化。常规治疗方案的有益效果是温和的，复发是恒定的。因此，迫切需要开发比目前可用的抗骨髓瘤疗法更有效的抗骨髓瘤疗法。最近提出了一种治疗骨髓瘤的全新方法，该方法基于骨髓瘤细胞对蛋白酶体活性的高度敏感性，蛋白酶体是负责许多重要转录因子降解的细胞内机制。蛋白酶体抑制作为一种新的靶向治疗方法，在患者中产生了显著的抗肿瘤效果。PS-341由Millennium Pharmaceuticals开发，现在被称为Bortezalide，抑制26 S蛋白酶体，并在20%的晚期骨髓瘤患者中产生缓解。这一显著进展导致FDA快速跟踪PS-341。然而，缓解持续时间短，药物是静脉注射。为了弥补这些缺点，我们研究了一系列在体外和体内表现出抗骨髓瘤作用的蛋白酶体抑制剂，并重点研究了环氧霉素，一种有效的、天然的、细胞可渗透的化合物，其选择性地和不可逆地抑制蛋白酶体活性，并且可以口服。Epoxomicin应该比PS-341具有实质性的临床优势。将在两种临床前治疗环境中证明环氧霉素在减少骨髓瘤肿瘤负荷和伴随的骨质溶解方面的疗效和安全性。第一种是骨髓瘤的预防性模型，其中在小鼠接种骨髓瘤细胞时开始给予环氧霉素（对应于临床缓解期或平台期的患者），第二种是治疗模型，其中在肿瘤建立后开始给予。目的1：评价环氧霉素对骨髓瘤进展的影响。目的2：评价环氧霉素对骨髓瘤所致溶骨性骨病变发生、发展的影响。目的3：确定环氧霉素对后肢麻痹发作时间的影响，后肢麻痹是生存的替代标志物。目的4：将口服环氧霉素的循环水平与抗骨髓瘤疗效相关联。将通过详细的骨骼和软器官组织学、外周血细胞计数、骨髓和肝功能以及血清化学评估来确定化合物的安全性。这些研究应该证明环氧霉素作为一种新的有效的治疗药物治疗骨髓瘤患者的潜力，具有显着更大的特异性，疗效和易用性比目前的治疗方式。

DESCRIPTION (provided by applicant): The goal of this proposal is to establish the efficacy and safety of epoxomicin as a potential therapy for the treatment of multiple myeloma, an incurable neoplasm affecting 70,000 Americans, accruing 15,000 new cases yearly, and accounting for 1-2% of cancer-related deaths. It is uniformly fatal, with eighty percent of patients suffering from devastating and progressive bone destruction. The average life span after diagnosis is less than three years, and this has not changed significantly over the past 30 years. Beneficial effects of conventional therapeutic regimens are modest and relapse is invariable. Therefore, there is an urgent need to develop anti-myeloma therapies that are more effective than those currently available. An entirely new approach has recently been suggested for the treatment of myeloma based on the exquisite sensitivity of myeloma cells to the activity of the proteasome, the intracellular machinery responsible for the degradation of many important transcription factors. Proteasome inhibition, as a novel targeted therapeutic approach, is causing substantial and remarkable anti-tumor effects in patients. PS-341, being developed by Millennium Pharmaceuticals and now called Bortezomib, inhibits the 26S proteasome and produces remissions in 20% of patients with advanced myeloma. This notable advance has led to fast-tracking of PS-341 by the FDA. However, remissions are of short duration and the drug is given intravenously. In efforts to remedy these shortcomings, we have examined a series of proteasome inhibitors that exhibit anti-myeloma effects in vitro and in vivo and have focused on epoxomicin, a potent, natural, cell-permeable compound that selectively and irreversibly inhibits proteasome activity and can, potentially to advantage, be given orally. Epoxomicin should convey substantive clinical advantages over PS-341. Efficacy and safety of epoxomicin in reducing myeloma tumor burden and concomitant osteolysis will be demonstrated in two preclinical treatment settings. The first, a preventative model of myeloma, where administration of epoxomicin commences at the time mice are inoculated with myeloma cells (corresponding to patients in clinical remission or plateau phase) and second, a treatment model where administration commences after the tumor is established. Aim 1: Evaluate the effect of epoxomicin on myeloma tumor progression. Aim 2: Evaluate the effect of epoxomicin on the development and progression of myeloma induced osteolytic bone lesions. Aim 3: Determine the effects of epoxomicin on the time to onset of hind-limb paralysis, a surrogate marker of survival. Aim 4: Correlate circulating levels of orally administered epoxomicin with anti-myeloma efficacy. Safety of the compound will be determined by detailed skeletal and soft organ histology, assessment of peripheral blood counts, bone marrow and liver function and serum chemistry. These studies should demonstrate the potential of epoxomicin as a new and effective therapeutic agent for treatment of myeloma patients, with substantially greater specificity, efficacy and ease of use than current treatment modalities.