MDC-1231 for cancer prevention

描述（由申请人提供）：结肠癌的化学预防一直受到弱剂或显著副作用的阻碍。最近的研究表明，舒林酸与二氟甲基鸟氨酸（DFMO）联合使用可以预防近70%的结肠癌，评估为结肠息肉复发。然而，舒林达克有频繁和显著的副作用，这使得它在癌症预防方面的长期应用存在问题。我们的I期STTR评估了我们的舒林达样化合物MDC-1231（也称为磷酸舒林达（PS））在结肠癌预防中的潜在作用。与舒林酸相比，PS具有更高的效力和安全性，并与DFMO协同作用以91%的效率预防结肠癌。我们的目标是在成功联合DFMO的情况下，用PS替代舒林酸，从而开发出一种更好的结肠癌预防方法。我们已经完成了第一阶段拨款的所有目标。目前II期申请的目标是完成PS的临床前开发并提交FDA IND申请。我们提出了五个具体目标，其中一些目标将并行实现，并相互影响。具体目标1：完成代谢方面的研究；对优化后的PS口服制剂进行PK/PD和生物分布。具体目标2：在GMP条件下扩大PS的合成规模。具体目标#3：开发PS的口服配方并确定其稳定性。具体目标#4：进行PS的毒性研究；它们包括动物毒性和遗传毒性研究。具体目标#5：准备IND方案和包装以提交FDA。这项工作如果成功，将为人类结肠癌化学预防的现实策略做出巨大贡献。

DESCRIPTION (provided by applicant): The chemoprevention of colon cancer has been hampered by either weak agents or significant side effects. It was recently shown that the combination of sulindac with difluoromethylornithine (DFMO) prevents nearly 70% of colon cancer, assessed as colon polyp recurrence. Sulindac, however, has frequent and significant side-effects that make its long-term application to cancer prevention problematic. Our phase I STTR assessed the potential role of our sulindac-like compound MDC-1231, also known as phosphosulindac (PS), in colon cancer prevention. PS has increased potency and safety compared to sulindac and acts synergistically with DFMO to prevent colon cancer with an efficacy of 91%. Our goal is to replace sulindac with PS in the successful combination with DFMO in order to develop a superior approach to colon cancer prevention. We have accomplished all the goals of the phase I grant. The goal of the present phase II application is to complete the preclinical development of PS and submit an FDA IND application. We propose five specific aims, some of them will be pursued in parallel and influence each other. Specific Aim #1: Complete the studies on the metabolism; perform PK/PD and biodistribution of the optimized oral formulation of PS. Specific Aim #2: Scale up the synthesis of PS under GMP conditions. Specific Aim #3: Develop an oral formulation of PS and determine its stability. Specific Aim #4: Perform toxicity studies of PS; they include animal toxicity and genotoxicity studies. Specific Aim #5: Prepare an IND protocol and package for FDA submission. The proposed work, if successful, will contribute greatly towards a realistic strategy for human colon cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Colon cancer is a major cause of cancer deaths in the US and worldwide. The prevention of colon cancer using pharmacological agents is now a realistic possibility, but new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially a highly effective and safe chemopreventive agent. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.