Riluzole Prodrugs for Melanoma and ALS

描述（由申请人提供）：转移性黑色素瘤的治疗选择很少，目前的治疗标准是达卡巴嗪，这是一种高度细胞毒性的药物，有严重的副作用，包括呕吐、头痛和脱发。达卡巴嗪治疗的中位无进展延长生存时间仅为1.5个月。利鲁唑（RilutekTM）是一种无毒药物，也是fda批准的唯一治疗肌萎缩性侧索硬化症（ALS或Lou Gehrig's disease）的药物。我们最近在体外、小鼠和人体0期临床试验中表明，利鲁唑具有显著的抗黑色素瘤活性。在临床中，12例黑色素瘤患者中有4例表现出明显的III期和IV期肿瘤反应的临床或放射学证据。这些结果，以及利鲁唑在ALS患者中显示的轻微副作用，表明该药物具有显著的潜力，可用于改善转移性黑色素瘤的治疗。然而，利鲁唑本身在ALS中的治疗效用以及最终对黑色素瘤的治疗效用受到肝脏快速首过代谢和观察到的cyp1a2介导的氧化代谢程度在患者之间异常高水平的可变性的限制。我们建议采用一种策略来解决这一问题，即利鲁唑的前药通过口服给药进入体循环，然后通过酶或一般生物物理释放过程在血浆中释放利鲁唑。将制备四种不同系列的利鲁唑前药，并评估其在不同ph值、模拟胃液和肠液、血清以及大鼠和人肝微粒体中的化学和酶稳定性。前药具有一系列的稳定性和裂解谱，但通常预测t1/2值为1-4小时，将使用我们之前用于评估利鲁唑的体外和小鼠黑色素瘤试验来评估抗黑色素瘤活性。利鲁唑、前药和载体治疗动物的比较将确定单个前药治疗黑色素瘤的疗效优势（ED50）。完整的药代动力学分析将改善药物暴露、清除和生物半衰期。我们的目标是通过成功应用利鲁唑前药策略来解决目前利鲁唑本身的药物代谢和分布限制，重新定位以利鲁唑为基础的治疗转移性黑色素瘤。

DESCRIPTION (provided by applicant): Metastatic melanoma has few treatment options, and the current therapeutic standard of care is dacarbazine which is a highly cytotoxic drug with severe side effects including vomiting, headache and hair loss. Treatment with dacarbazine has a median progression-free enhancement of survival time of only 1.5 months. Riluzole (RilutekTM) is a non-toxic drug and the only FDA-approved treatment for amytrophic lateral sclerosis (ALS or Lou Gehrig's disease). We have recently shown that riluzole has dramatic anti-melanoma activity in vitro, in mice and in a Phase 0 human clinical trial. In the clinic, four of twelve melanoma patients showed significant clinical or radiologic evidence of Stage III and IV tumor response. These results, along with the mild side-effect profile that riluzole has shown among ALS patients, suggests that this drug has significant potential for use as an improved treatment for metastatic melanoma. However, the therapeutic utility of riluzole itself in ALS and eventually for melanoma is very constrained by rapid first-pass metabolism in the liver and an exceptionally high level of patient-to-patient variability in the extent of the Cyp1A2-mediated oxidative metabolism that is observed. We propose to solve this problem using a strategy in which prodrugs of riluzole having enhanced stability to hepatic metabolism are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. Four different series of riluzole prodrugs will be prepared and evaluated for their chemical and enzymatic stability at differing pHs, in simulated gastric and intestinal fluid, in serum, and in rat and human liver microsomes. Prodrugs having a range of stability and cleavage profiles, but generally with projected t1/2 values of 1-4 hrs, will be evaluated for anti- melanoma activity using the same in vitro and murine melanoma assays which we have previously used to evaluate riluzole. Comparison of riluzole-, prodrug- and vehicle-treated animals will establish the advantage in efficacy (ED50) of individual prodrugs against melanoma. Full pharmacokinetic analysis will establish improvements in drug exposure, clearance and biological half-life. Our goal is to reposition riluzole-based therapy for the treatment of metastatic melanoma by the successful application of a prodrug strategy to solve the current drug metabolism and distribution limitations of riluzole itself. PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a type of cancer having extremely low survival rates and very limited treatment options based on highly toxic chemotherapy agents. Riluzole is a non- toxic drug approved for amyotrophic lateral sclerosis (ALS). We have recently shown exciting preliminary results for riluzole treatment of metastatic melanoma in mice and human subjects. But because of differences in how individuals metabolize riluzole, it will be difficult for this drug to realize its full potential as a treatment for metastatic melanoma. In this application, we propose to design, synthesize and evaluate novel drug candidates which will release riluzole in a more predictable and longer-acting way, leading to improved therapies for metastatic melanoma.