DEVELOPMENT OF A WNT PATHWAY INHIBITOR FOR METASTATIC COLORECTAL CANCER

转移性结直肠癌 WNT 通路抑制剂的开发

• 批准号: 9761463
• 负责人: Darren Orton
• 金额: $ 100万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761463
• 关键词: Adult; Advanced Malignant Neoplasm; Adverse effects; Animal Model; Antineoplastic Agents; Architecture; Area; Award; Biological Assay; Biological Markers; Biological Products; Biology; Biopsy Specimen; Biotechnology; Businesses; Cancer Patient; Capital; Cell Survival; Cessation of life; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Colon; Colorectal Cancer; Complex; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Dose-Limiting; Drug Targeting; Ensure; Epithelial; Epithelium; Erinaceidae; FDA approved; Funding; Generations; Genetic Models; Genetic Transcription; Goals; Growth; Homeostasis; Howard Temin Award; Human; In Vitro; International; Intestines; KRAS2 gene; Laboratories; Lead; Malignant Neoplasms; Mammals; Maximum Tolerated Dose; Mission; Modeling; Monkeys; Mus; Mutation; Normal tissue morphology; Nuclear; Oncogenic; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Play; Population; Preparation; Process; Progressive Disease; Public Health; Regimen; Reporter; Rodent; Role; Safety; Schedule; Science; Seasons; Small Business Innovation Research Grant; Somatic Mutation; Stage at Diagnosis; Stem cells; TP53 gene; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Villus; WNT Signaling Pathway; Work; Xenograft Model; cancer cell; cancer diagnosis; cancer stem cell; cancer subtypes; casein kinase I; clinical candidate; colon cancer cell line; colon cancer patients; colorectal cancer progression; colorectal cancer treatment; commercialization; disease phenotype; druggable target; effective therapy; efficacy study; experience; improved; in vivo; inhibitor/antagonist; innovation; meetings; metastatic colorectal; molecular targeted therapies; mouse model; multidisciplinary; nonhuman primate; notch protein; novel; novel therapeutic intervention; oncology; outcome forecast; pre-clinical; preclinical development; preclinical trial; progenitor; programs; research and development; safety study; self-renewal; small molecule; targeted agent; tool; tumor xenograft; tumorigenesis

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.

抽象的 结直肠癌（CRC）代表第四常见的癌症，每个癌症都有134,490例新病例 年。不幸的是，由于CRC导致死亡人数不成比例（2016年预计为49,190） 诊断后的高级阶段，疾病的积极表型和缺乏有效的治疗。更大 在WNT信号通路中具有活化突变的CRC患者中，超过90％。 Wnt途径激活 是启动CRC肿瘤发生的关键步骤。目前，没有FDA批准的药物或药物 在针对WNT途径的后期临床试验中。结果，这迫切需要 WNT途径的抑制剂的发展不仅治疗CRC，还可以治疗其他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 以及针对关键癌症干细胞（包括Wnt）的新型热方法的商业化 刺猬和缺口。 SSTI鉴定了一类小分子，这些分子通过激活调节Wnt信号传导 在此应用中，酪蛋白激酶1的作用机理的详细表征， 演示在CRC中发现的激活突变下游的SST-215功能，可产生优秀的体外 在一系列CRC细胞系中的效力，并使用各种遗传和 小鼠的异种移植模型。值得注意的是，SST-215不影响正常的胃肠道结构，这与 目前正在开发GI毒性的另外两种主要类别的WNT抑制剂是剂量限制的。这 IIB阶段应用程序概述了SST-215开发的下一个逻辑步骤：啮齿动物的完成和 非旋转安全研究，ID的准备和I期临床试验的先进或转移性试验的启动 癌症。成功完成此阶段IIB项目将为进步提供所有必要的研究 概念证明在人类中的II期有效性研究并完成了SBIR计划的使命 支持小型企业将创新的解决方案推向主要的公共卫生问题。 Wnt途径在许多不同的癌症亚型中起作用，并且因为市场上没有药物 通过继续将SST-215通过肿瘤学开发管道，SSTI，针对WNT途径 有可能改善和延长全球数百万癌症患者的寿命。多学科 SSTI的研发团队在所有相关领域都有良好的资格和经验，使我们能够完成钥匙 发展的科学和业务方面。作为我们商业化计划的一部分，SSTI正在合作 与Geneyus，LLC（由三个季节资本资助）为此应用提供匹配资金，以及 SSTI的大量后续商业化资金符合此处概述的里程碑。在 总结，我们提供了强大的临床前数据，支持分子靶向，治疗效率和 SST-215的初步安全研究证明过渡到下一个发展阶段，非人类灵长类动物 安全研究和I期临床试验。支持此阶段IIB应用程序将确保SST-215确实 不屈服于由于资金而屈服于发展的延误，并将支持SSTI推销第一代 WNT抑制剂捕获了全球癌症药物市场的很大一部分。