Improved Treatment of Colorectal Cancer with CF10

项目摘要 数十年来，通过时间表优化来调节氟嘧啶药物（FP）的抗癌活性， 生物化学调节和药物组合提供了一个显着的，但有限的，生存优势， 治疗患有局部晚期或转移性疾病（mCRC）的结直肠癌（CRC）患者。然而，在这方面， mCRC患者的结局仍然很差，因为靶向治疗和免疫治疗仅提供 由于对一部分CRC患者的益处有限，因此迫切需要新的方法。深溪制药 一起学术合作伙伴维克森林医学院（WFSM）正在开发CF 10，第一个基于DNA的 FP聚合物，作为CRC的改进治疗。在通过1期STTR支持的临床前研究中，我们 证明CF 10对CRC细胞比5-FU有效得多，并证明存活率提高 相对于5-FU，在啮齿动物的多种结肠肿瘤模型中。此外，CF 10显示出降低的全身毒性 相对于5-FU，使其成为临床开发的强有力候选物。我们还建立了CF 10显示器 相对于常规FP药物，具有独特的药理学和机制特性。根据这些发现， DeepCreek Pharma和WFSM/Gmeiner Lab提议联合研究CF 10作为临床候选药物 发展 一个主要的未满足需求是治疗FOLFOX（5-FU、甲酰四氢叶酸（LV）、奥沙利铂）难治性mCRC， mCRC的其他一线疗法。因此，第二阶段的拟议研究将侧重于（目标1）开发 CF 10脂质纳米颗粒（LNP）和改善活性的测试，包括在耐药性CRC肝脏中 转移模型LNP制剂已被证明是多种核酸药物的稳健递送策略， 并且确定优选的LNP制剂将促进CF 10的临床开发。第二阶段的目标2 我们将在啮齿动物中进行CF 10和CF 10：LNP的安全药理学研究，而在目标3中，我们将 评价非人灵长类动物（NHP）的药代动力学（PK）和生物分布。NHP研究准确 反映人体生理学和代谢，对调节评估特别重要。总体而言，我们 II期STTR研究将为推进CF 10进入临床试验提供关键数据， 商业化

PROJECT SUMMARY Decades of modulating the anti-cancer activity of fluoropyrimidine drugs (FPs) thru schedule optimization, biochemical modulation, and drug combinations have provided a significant, but limited, survival advantage for treating colorectal cancer (CRC) patients with locally advanced or metastatic disease (mCRC). However, outcomes remain poor for patients with mCRC and since targeted therapies and immunotherapies provide only a limited benefit to a sub-set of CRC patients, new approaches are urgently needed. Deep Creek Pharma together academic partner Wake Forest School of Medicine (WFSM) is developing CF10, the first DNA-based FP polymer, as an improved treatment for CRC. In pre-clinical studies through Phase 1 STTR support, we have demonstrated that CF10 is much more potent than 5-FU to CRC cells and demonstrated improved survival relative to 5-FU in multiple colon tumor models in rodents. Further, CF10 displayed reduced systemic toxicities relative to 5-FU making it a strong candidate for clinical development. We have also established CF10 displays distinct pharmacological and mechanistic properties relative to conventional FP drugs. Based on these findings, DeepCreek Pharma and WFSM/Gmeiner Lab propose to jointly investigate CF10 as a candidate for clinical development. A major unmet need is treatment of mCRC that is refractory to FOLFOX (5-FU, Leucovorin (LV), oxaliplatin), and other front-line therapies for mCRC. The proposed research in phase II will therefore focus on (Aim 1) Developing CF10 lipid nanoparticles (LNPs) and testing for improved activity, including in a therapy-resistant CRC liver metastasis model. LNP formulation has proven to be a robust delivery strategy for multiple nucleic acid drugs, and identifying a preferred LNP formulation will promote CF10 clinical development. In Aim 2 of the Phase II studies we will perform safety pharmacology studies of CF10 and CF10:LNPs in rodents while in Aim 3 we will evaluate pharmacokinetics (PK) and biodistribution in non-human primates (NHPs). Studies in NHPs accurately reflect human physiology and metabolism and are particularly important for regulatory apprval. Collectively, our Phase II STTR studies will provide critical data for to advance CF10 into clinical trials and ultimately its commercialization.