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提供了一个重要但有限的生存优势 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。使用一种简单的纳米颗粒 聚合5FU活性代谢物5-氟-2‘-脱氧尿苷-5’-O-单磷酸的设计 (FdUMP)，为了创造单链DNA FP均聚物，维克森林医学院(WFSM)的Gmeiner实验室 结果表明，与5-羟色胺相比，可提高抗肿瘤活性并减少全身毒性。 阿福。这种方法改变了传统药物的药理特性、生物分布和新陈代谢。 FPS。第二代FP聚合物CF10，经过化学修饰以提高对酶的稳定性 在多个CRC细胞系中进行了测试，并显示出相对于 原型FP聚合物F10。CF10在体内耐受性好，定位于原位结肠肿瘤，并显示 在原位结肠癌模型中有很强的抗肿瘤活性，有希望的抗转移活性。基于 这些发现，DeepCreek Pharma和WFSM/Gmeiner Lab建议联合调查CF10作为候选 用于临床开发。 第一阶段的拟议研究将集中于(目标1)测试CF10是否比F10或5-FU更有效 抑制结直肠癌的转移进展，包括胸苷合成酶过表达(TS)的结直肠癌，即5- 耐FU。这一点很重要，因为转移性疾病是结直肠癌致死的原因，而TS升高是一种 5-FU耐药的原因，并可能有助于转移疾病的进展。(目标2)将重点放在 在大鼠同基因结直肠癌肝转移模型中，CF10显示出更好的抗转移活性。 这些研究将量化CF10和FP代谢物的生物分布，并测试CF10的输入量是否增加 摄取到胃肠道(GI)而不损害非恶性组织。临床分级的翻译 DeepCreek Pharma生产的CF10将进入治疗mCRC的临床试验，这将是下一个阶段 这个STTR项目。

PROJECT SUMMARY Decades of modulating the anti-cancer activity of fluoropyrimidine drugs (FPs) thru schedule optimization, biochemical modulation, and drug combinations have provided an important, 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. Using a simple nanoparticle design consisting of polymerizing 5FU’s active metabolite, 5-fluoro-2’-deoxyuridine-5’-O-monophosphate (FdUMP), to create ssDNA FP homopolymers, the Gmeiner lab at Wake Forest School of Medicine (WFSM) demonstrated that improved anti-tumor activity and reduced systemic toxicities could be achieved relative to 5- FU. This approach alters pharmacological properties, biodistribution, and metabolism relative to conventional FPs. A 2nd generation FP polymer, CF10, that is chemically modified to improve stability to enzymatic degradation, was tested in multiple CRC cell lines and displayed further improved potency relative to the prototype FP polymer F10. CF10 is well tolerated in vivo, localizes to orthotopic colon tumors, and displays strong anti-tumor activity in an orthotopic colon cancer model and promising anti-metastatic activity. Based on these findings, DeepCreek Pharma and WFSM/Gmeiner Lab propose to jointly investigate CF10 as a candidate for clinical development. The proposed research in phase I will focus on (Aim 1) testing if CF10 is more effective than either F10 or 5-FU at inhibiting CRC metastatic progression, including in thymidylate synthase overexpressing (TS+) CRC that is 5- FU resistant. This is important because metastatic disease is the cause of CRC lethality and elevated (TS) is a cause of 5-FU resistance and may contribute to progression of metastatic disease. (Aim 2) will focus on demonstrating CF10 displays improved anti-metastatic activity in a rat, syngeneic CRC liver metastasis model. These studies will quantify the biodistribution of CF10 and FP metabolites and test if infusion of CF10 increases uptake into the gastrointestinal (GI) tract without damaging non-malignant tissues. Translation of clinical grade CF10 produced by DeepCreek Pharma into clinical trials for treating mCRC would be the next stage following this STTR project.