Improved Treatment of Colorectal Cancer with CF10

项目总结 几十年来，通过优化方案来调节氟嘧啶类药物(FP)的抗癌活性， 生化调节和药物组合为患者提供了显著但有限的生存优势。 治疗患有局部晚期或转移性疾病的结直肠癌(CRC)患者。然而， 转移性结直肠癌患者的预后仍然很差，因为靶向治疗和免疫疗法只能提供 虽然对部分结直肠癌患者的益处有限，但迫切需要新的治疗方法。深溪制药 学术合作伙伴维克森林医学院(WFSM)正在开发第一个基于DNA的CF10 FP聚合物，作为一种改进的结直肠癌治疗方法。在通过第一阶段STTR支持进行的临床前研究中，我们有 证明CF10比5-FU对结直肠癌细胞有更强的杀伤作用，并显示出提高存活率的作用 在啮齿动物多发性结肠癌模型中相对于5-FU。此外，CF10显示出较低的全身毒性 相对于5-FU，使其成为临床开发的有力候选者。我们还建立了CF10显示器 与传统的FP药物相比，具有独特的药理和机制特性。基于这些发现， DeepCreek Pharma和WFSM/Gmeiner Lab提议联合调查CF10作为临床候选 发展。 一个尚未得到满足的主要需求是治疗对FOLFOX(5-FU、亚叶酸钙(LV)、奥沙利铂)无效的mCRC，以及 多发性结直肠癌的其他一线治疗。因此，第二阶段的拟议研究将侧重于(目标1)开发 CF10脂质纳米粒(LNPs)和改善活性的测试，包括在治疗耐药的CRC肝脏中 转移模型。LNP制剂已被证明是多种核酸药物的一种稳健的递送策略， 确定首选的LNP配方将促进CF10的临床开发。在第二阶段的目标2中 研究我们将在啮齿动物身上进行CF10和CF10：LNPs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的药代动力学(PK)和生物分布。NHP中的研究准确 反映人体生理和新陈代谢，对调节作用尤为重要。总的来说，我们的 第二阶段STTR研究将为推动CF10进入临床试验并最终实现其 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.