MDC-1231 for cancer prevention

描述（由申请人提供）：结肠癌的化学预防受到弱药剂或显著副作用的阻碍。最近表明，舒林酸与二氟甲基鸟氨酸（DFMO）的组合预防了近70%的结肠癌，被评估为结肠息肉复发。然而，舒林酸具有频繁且显著的副作用，这使得其长期应用于癌症预防存在问题。我们的I期STTR评估了我们的舒林酸样化合物MDC-1231（也称为磷酸舒林酸（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，以预防结肠癌，有效性为91%。我们的目标是在成功的组合DFMO中用PS取代舒林酸，以开发一种上级结肠癌预防方法。我们已经实现了第一阶段赠款的所有目标。本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，其中一些目标将平行进行，并相互影响。具体目标#1：完成代谢研究;对优化的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。具体目标#3：开发PS的口服制剂并确定其稳定性。具体目标#4：进行PS的毒性研究;包括动物毒性和遗传毒性研究。具体目标#5：准备IND方案和文件包以供FDA提交。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。 公共卫生相关性：结肠癌是美国和全球癌症死亡的主要原因。使用药理学试剂预防结肠癌现在是现实的可能性，但迫切需要新的试剂。我们建议开发一种新的化合物，磷酸-舒林酸，这是一种潜在的高效和安全的化学预防剂。预期的结果将为完成磷酸-舒林酸的临床前评估铺平道路，这是在人体测试之前的一个必要步骤。

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.