Improved Treatment of Colorectal Cancer with CF10

CF10 改善结直肠癌治疗

• 批准号: 10254547
• 负责人: William H Gmeiner
• 金额: $ 39.64万
• 依托单位: DEEP CREEK PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254547
• 关键词: Affect; Aftercare; Animal Model; Bile fluid; Biochemical; Biodistribution; Blood; Bolus Infusion; Businesses; Cancer Etiology; Cancer Model; Catheters; Cell Line; Cessation of life; Characteristics; Chemicals; Clinical Research; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Deoxyuridine; Development; Dimensions; Disease; Disease Resistance; Drug Combinations; Drug Kinetics; Exonuclease; Fluorouracil; Foundations; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Generations; HCT116 Cells; Hematology; Hepatobiliary; Hepatotoxicity; Immunologics; Immunotherapy; Infusion procedures; Laboratories; Liver; Malignant neoplasm of liver; Metabolism; Metastatic Neoplasm to the Liver; Modeling; Modification; Mus; Nanotechnology; Non-Malignant; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Polyethylene Glycols; Polymers; Pre-Clinical Model; Property; Rattus; Regimen; Research; Resistance; Schedule; Single-Stranded DNA; Small Business Technology Transfer Research; Structure of jugular vein; System; Technology Transfer; Testing; Tetanus Helper Peptide; Therapeutic; Thymidylate Synthase; Time; Tissue Sample; Tissues; Toxic effect; Translating; anticancer activity; antitumor agent; base; cancer cell; chemotherapy; clinical candidate; clinical development; clinical translation; clinically relevant; colon cancer cell line; colon cancer patients; colorectal cancer metastasis; colorectal cancer treatment; design; efficacy testing; fluoropyrimidine; forest; improved; improved outcome; in vivo; innovation; medical schools; metastatic colorectal; mortality; nanoparticle; nanoscale; non-Native; novel; novel strategies; nucleoside analog; overexpression; prototype; systemic toxicity; targeted treatment; tumor; uptake

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.

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重要的，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。使用一个简单的纳米粒子 设计包括聚合5 FU的活性代谢物，5-氟-2 '-脱氧尿苷-5'-O-单磷酸 （FdUMP），创造ssDNA FP均聚物，Gmeiner实验室在维克森林医学院（WFSM） 证明了相对于5-羟基喹啉，可以实现改善的抗肿瘤活性和降低的全身毒性。 Fu.这种方法相对于常规方法改变了药理学性质、生物分布和代谢。 FP。第二代FP聚合物CF 10，经过化学改性，可提高对酶的稳定性 在多个CRC细胞系中测试了降解，并显示出相对于对照组进一步改善的效力。 原型FP聚合物F10。CF 10在体内耐受性良好，定位于原位结肠肿瘤，并表现出 在原位结肠癌模型中具有强的抗肿瘤活性和有希望的抗转移活性。基于 根据这些发现，DeepCreek Pharma和WFSM/Gmeiner Lab提议联合研究CF 10作为候选药物 用于临床开发。 如果CF 10比F10或5-FU更有效，则I期拟议研究将侧重于（目标1）测试 在抑制CRC转移进展方面，包括在胸苷酸合酶过表达（TS+）CRC中，其为5- FU耐药。这一点很重要，因为转移性疾病是CRC致死性的原因，而升高的（TS）是导致CRC死亡的主要原因。 5-FU耐药的原因，并可能导致转移性疾病的进展。(Aim（2）重点 证明CF 10在大鼠同基因CRC肝转移模型中显示出改善的抗转移活性。 这些研究将量化CF 10和FP代谢物的生物分布，并检测CF 10输注是否增加 吸收进入胃肠道（GI）而不损害非恶性组织。临床等级翻译 由DeepCreek Pharma生产的用于治疗mCRC的CF 10将是下一阶段 这个STTR项目