DEVELOPMENT OF A WNT PATHWAY INHIBITOR FOR METASTATIC COLORECTAL CANCER

摘要 结直肠癌（CRC）是第四大最常见的癌症，每种癌症有134，490例新发病例 年不幸的是，CRC导致的死亡人数不成比例（2016年预计为49，190人），原因是 诊断时的晚期、疾病的侵袭性表型和缺乏有效的治疗方法。更大 超过90%的CRC患者在WNT信号通路中具有激活突变。WNT途径激活 是CRC肿瘤发生起始的关键步骤。目前，没有FDA批准的药物或药物 在针对WNT通路的后期临床试验中。因此，迫切需要 开发WNT通路的抑制剂，不仅治疗CRC，还治疗其他WNT驱动的癌症。 StemSynergy Therapeutics Inc.（SSTI）是一家生物制药公司，专注于发现，开发 以及靶向关键癌症干细胞的新型治疗方法的商业化，包括WNT， 刺猬和缺口。SSTI已经确定了一类通过激活WNT信号调节WNT信号的小分子， 在本申请中，我们描述了作用机制的详细表征， 证明SST-215在CRC中发现的激活突变的下游发挥作用， 在一系列CRC细胞系中的效力，并使用各种遗传和 小鼠异种移植模型。值得注意的是，SST-215不会影响正常的GI结构，这与 目前正在开发的另外两种主要类型的WNT抑制剂，其中GI毒性是剂量限制性的。这 IIb期申请概述了SST-215开发的下一个逻辑步骤：完成啮齿动物和 非啮齿类动物安全性研究、IND制备和启动晚期或转移性肿瘤的I期临床试验 癌成功完成IIb期项目将提供所有必要的研究进展 在人类中进行概念验证II期疗效研究，并完成SBIR计划的使命， 支持小企业为重大公共卫生问题提出创新解决方案。 WNT通路在许多不同的癌症亚型中发挥作用， 通过继续将SST-215通过肿瘤学开发管道SSTI， 有可能改善和延长全世界数百万癌症患者的生命。多学科 SSTI的研发团队在所有相关领域都有很强的资历和经验，使我们能够完成关键的 科学和商业方面的发展。作为我们商业化计划的一部分，SSTI正在与 与Geneyus，LLC（由三季资本资助）合作，为该申请提供匹配资金，以及 重要的后续商业化资金取决于SSTI满足此处概述的里程碑。在 总之，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了过渡到下一个开发阶段的合理性，非人灵长类动物 安全性研究和I期临床试验。对IIb期应用的支持将确保SST-215 不屈服于由于资金而导致的开发延迟，并将支持SSTI将第一代产品推向市场 WNT抑制剂，以占领全球抗癌药物市场的重要份额。

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.