Preclinical Efficacy of Epoxomicin in Multiple Myeloma

Epoxomicin 在多发性骨髓瘤中的临床前疗效

• 批准号: 6688400
• 负责人: I ROSS GARRETT
• 金额: $ 10万
• 依托单位: OSTEOSCREEN, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688400
• 关键词: antineoplastics; apoptosis; blood chemistry; charge coupled device camera; drug screening /evaluation; enzyme linked immunosorbent assay; green fluorescent proteins; histology; laboratory mouse; morphometry; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic process; oligopeptides; osteosarcoma; pharmacokinetics; transcription factor

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.

描述（由申请人提供）：本提案的目标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，影响着 70,000 名美国人，每年新增 15,000 例新病例，占癌症相关死亡的 1-2%。它都是致命的，百分之八十的患者遭受毁灭性的​​、进行性的骨质破坏。确诊后的平均寿命不到三年，这一点在过去30年里没有显着改变。传统治疗方案的有益效果有限，并且复发是不可避免的。因此，迫切需要开发比现有疗法更有效的抗骨髓瘤疗法。最近，基于骨髓瘤细胞对蛋白酶体活性的高度敏感性，提出了一种用于治疗骨髓瘤的全新方法，蛋白酶体是负责降解许多重要转录因子的细胞内机制。蛋白酶体抑制作为一种新型靶向治疗方法，正在对患者产生显着的抗肿瘤效果。 PS-341 由 Millennium Pharmaceuticals 开发，现称为 Bortezomib，可抑制 26S 蛋白酶体，使 20% 的晚期骨髓瘤患者得到缓解。这一显着进展促使 FDA 对 PS-341 进行快速审批。然而，缓解时间很短，并且药物是静脉注射的。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，它是一种有效的、天然的、细胞渗透性化合物，可选择性且不可逆地抑制蛋白酶体活性，并且可以口服给药，具有潜在的优势。 Epoxomicin 应该比 PS-341 具有实质性的临床优势。环氧霉素在减少骨髓瘤肿瘤负荷和伴随的骨溶解方面的功效和安全性将在两种临床前治疗环境中得到证实。第一种是骨髓瘤的预防模型，在给小鼠接种骨髓瘤细胞时（对应于临床缓解或平台期的患者）开始给予环氧霉素；第二种是治疗模型，在肿瘤建立后开始给予。目标 1：评估环氧霉素对骨髓瘤肿瘤进展的影响。目标 2：评估环氧霉素对骨髓瘤引起的溶骨性骨病变发生和进展的影响。目标 3：确定环氧霉素对后肢麻痹发作时间（生存的替代标志）的影响。目标 4：将口服环氧霉素的循环水平与抗骨髓瘤功效相关联。该化合物的安全性将通过详细的骨骼和软器官组织学、外周血计数、骨髓和肝功能以及血清化学的评估来确定。这些研究应证明环氧霉素作为治疗骨髓瘤患者的新型有效治疗剂的潜力，与目前的治疗方式相比，具有更高的特异性、功效和易用性。