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）：该提案的目的是确定环氧素的疗效和安全性，作为治疗多发性骨髓瘤的潜在疗法，一种影响70,000名美国人的可治疗肿瘤，每年累计15,000例新病例，并计算与癌症相关的死亡1-2％。它是统一的致命性，其中80％的患者患有毁灭性和进行性骨骼破坏。诊断后的平均寿命小于三年，在过去30年中，这种寿命没有发生显着变化。常规治疗方案的有益作用适中，复发是不变的。因此，迫切需要开发出比当前可用的抗肌瘤疗法更有效的。最近，基于骨髓瘤细胞对蛋白酶体的活性的敏感性（造成许多重要转录因子降解的细胞内机制）的敏感性，最近提出了一种全新的方法来治疗骨髓瘤。作为一种新型的靶向治疗方法，蛋白酶体抑制作用正在引起患者的实质性和显着的抗肿瘤作用。 PS-341是由千年药品开发的，现在称为硼替佐米，抑制了26S蛋白酶体，并在20％的晚期骨髓瘤患者中抑制了26S蛋白酶体。这一显着的进步导致FDA对PS-341进行了快速跟踪。但是，恢复持续时间短，药物是静脉内给予的。为了解决这些缺点，我们检查了一系列蛋白酶体抑制剂，这些蛋白酶体抑制剂在体外和体内表现出抗肌瘤作用，并专注于环氧素蛋白，一种有效的，天然的，可自然的，可渗透性的化合物，有选择地，有选择性地和不可逆地抑制蛋白酶体的活性，并且可以抑制蛋白酶体的活性，并有可能提供优势，可以口头或有优势。环氧素应传达与PS-341相比的实质性临床优势。环氧化物素对减轻骨髓瘤肿瘤负担和造骨溶解的功效和安全性将在两个临床前治疗环境中证明。第一个是骨髓瘤的预防模型，其中在时间小鼠时开始给予环氧化物素的骨髓瘤细胞（对应于临床缓解或高原阶段的患者），其次是一种治疗模型，其中一种治疗模型在肿瘤建立后开始。 AIM 1：评估环氧素对骨髓瘤肿瘤进展的影响。 AIM 2：评估环氧素对骨髓瘤诱导骨质骨病变的发育和进展的影响。 AIM 3：确定环氧化物素对Hind-Limb麻痹发作时间的影响，这是生存的替代标志。 AIM 4：将循环水平与抗肌瘤疗效相关。该化合物的安全性将由详细的骨骼和软器官组织学，外周血计数的评估，骨髓和肝功能以及血清化学确定。这些研究应证明，与当前的治疗方式相比，环氧素作为一种新的有效治疗剂治疗骨髓瘤患者的潜力。