DEVELOPMENT OF A WNT PATHWAY INHIBITOR FOR METASTATIC COLORECTAL CANCER

摘要 结直肠癌(CRC)是第四种最常见的癌症，每例新增病例134,490例 年。不幸的是，儿童权利公约导致了不成比例的死亡人数(预计2016年为49 190人)，原因是 诊断处于晚期，疾病的侵袭性表型和缺乏有效的治疗方法。更大 超过90%的结直肠癌患者存在WNT信号通路的激活突变。WNT途径激活 是启动结直肠癌发生的关键步骤。目前，还没有FDA批准的药物或药物 在针对WNT途径的晚期临床试验中。因此，这里迫切需要 开发WNT途径的抑制剂，不仅可以治疗结直肠癌，还可以治疗其他由WNT驱动的癌症。 StemSynergy Treateutics Inc.(SSTI)是一家专注于发现、开发 以及针对关键癌症干细胞的新治疗方法的商业化，包括WNT， 刺猬和诺奇。SSTI已经确定了一类通过激活来调节WNT信号的小分子 酪蛋白激酶1在本申请中，我们描述了作用机制的详细表征， 证明SST-215在激活CRC中发现的突变下游的功能，以在体外产生优秀的 在一系列结直肠癌细胞系中的效力，并提供显著的体内疗效数据，使用各种基因和 小鼠异种移植模型。值得注意的是，SST-215不影响正常的GI架构，这与 另外两类主要的WNT抑制剂目前正在开发中，其中胃肠道毒性是剂量限制的。这 第二阶段应用概述了制定SST-215的下一个合乎逻辑的步骤：完成啮齿动物和 非啮齿动物安全性研究、IND准备和启动晚期或转移的I期临床试验 癌症。这一第二阶段项目的成功完成将为进展提供所有必要的研究 在人体上进行概念验证第二阶段疗效研究，并完成SBIR计划的任务 支持小型企业针对重大公共卫生问题提出创新解决方案。 WNT途径在许多不同的癌症亚型中发挥作用，因为市场上还没有药物 通过继续通过肿瘤学发展管道SSTI移动SST-215来靶向WNT途径 有可能改善和延长全球数百万癌症患者的生命。多学科交叉 SSTI的研发团队在所有相关领域都拥有强大的资历和经验，使我们能够完成关键 科学和商业方面的发展。作为我们商业化计划的一部分，SSTI正在合作 与Geneyus，LLC(由Three Seasons Capital提供资金)为这项申请提供匹配资金，以及 重大的后续商业化资金取决于SSTI能否达到本文概述的里程碑。在……里面 综上所述，我们提供了强有力的临床前数据支持分子靶向、治疗效果和 SST-215的初步安全性研究证明有理由过渡到非人类灵长类动物的下一个发育阶段 安全性研究和I期临床试验。对这一IIb阶段应用的支持将确保SST-215 不会屈服于由于资金原因导致的开发延迟，并将支持SSTI将第一代产品推向市场 WNT抑制剂的使用将在全球抗癌药物市场占据相当大的份额。

ABSTRACT Colorectal cancer (CRC) represents the fourth most commonly diagnosed cancer with 134,490 new cases each year. Unfortunately, CRC results in a disproportionate number of deaths (49,190 projected in 2016) due to advanced stage at diagnosis, the aggressive phenotype of the disease and lack of effective therapeutics. Greater than 90% of CRC patients possess activating mutations in the WNT signaling pathway. WNT pathway activation is a critical step in the initiation of CRC tumorigenesis. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target the WNT pathway. As a result, here is an urgent need for the development of inhibitors of the WNT pathway to treat not only CRC, but other WNT-driven cancers. StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutic approaches to target critical cancer stem cells, including WNT, Hedgehog and Notch. SSTI has identified a class of small molecules that regulate WNT signaling via activation of Casein Kinase 1 In this application, we describe detailed characterization of mechanism of action, demonstrate SST-215 functions downstream of activating mutations found in CRC to produce excellent in vitro potency in a range of CRC cell lines and provide significant in vivo efficacy data using various genetic and xenograft models in mice. Significantly, SST-215 does NOT affect normal GI architecture, which is in contrast to two other major classes of WNT inhibitors currently being developed where GI toxicity is dose limiting. This Phase IIb application outlines the next logical steps in the development of SST-215: completion of rodent and non-rodent safety studies, IND preparation and initiation of a Phase I clinical trial for advanced or metastatic cancer. Successful completion of this Phase IIb project will provide all of the necessary studies for progression to proof-of-concept Phase II efficacy study in humans and accomplish the mission of the SBIR program of supporting small businesses in bringing forward innovative solutions to major public health concerns. The WNT pathway plays a role in many different cancer subtypes and because there are no drugs on the market that target the WNT pathway, by continuing to move SST-215 through the oncology development pipeline, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. The multi-disciplinary R&D team at SSTI has strong credentials and experience in all relevant areas, enabling us to complete the key science and business aspects of the development. As part of our commercialization plan, SSTI is collaborating with Geneyus, LLC (funded by Three Seasons Capital) to provide matching funds for this application, as well as significant follow-on commercialization funding contingent on SSTI meeting the milestones outlined herein. In summary, we provide strong preclinical data supporting the molecular targeting, therapeutic efficacy and preliminary safety studies for SST-215 justifying transition to the next stages of development, non-human primate safety studies and a phase I clinical trial. Support of this Phase IIb application will ensure that SST-215 does not succumb to delays in development due to funding and will support SSTI bringing to market a first generation of WNT inhibitors to capture a significant share of the global market for cancer drugs.