TASK ORDER TITLE: PREVENTING COLORECTAL CANCER USING TRAIL-INDUCING ONC201 ALONE OR IN COMBINATION WITH NSAID

任务单标题：单独使用 TRAIL 诱导 ONC201 或与 NSAID 联合使用预防结直肠癌

基本信息

批准号：
10269144
负责人：
CHINTHALAPALLY RAO
金额：
$ 87.95万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269144
关键词：
Adenocarcinoma Adenomatous Polyposis Coli ApcMin/+ mice Apoptosis Azoxymethane Biological Markers Cancer Cell Growth Cancer Etiology Canis familiaris Carcinoma Cardiotoxicity Cell Line Cell Proliferation Chemopreventive Agent Colon Colon Carcinoma Colonic Adenoma Colonic Neoplasms Colorectal Cancer Diet Dopamine Antagonists Dopamine D2 Receptor Dose Early Diagnosis Female Genetic Predisposition to Disease Growth HCT116 Cells Human In Vitro Incidence Individual Lesion Mediating Modeling Modification Naproxen Non-Steroidal Anti-Inflammatory Agents Normal Cell Oral Organoids Patients Pharmaceutical Preparations Prevention strategy Preventive Proto-Oncogene Proteins c-akt Rattus Recombinants Reporting Research Safety Sampling Schedule Small Intestinal Neoplasm Solid Neoplasm Stable Disease Stomach Sulindac TNF-related apoptosis-inducing ligand Testing Therapeutic Toxic effect Travel United States Xenograft procedure adenoma biological adaptation to stress cancer cell clinically translatable colorectal cancer prevention drug development in vivo male mortality mouse model phase I trial phase II trial polyposis premalignant

项目摘要

Despite significant advances in early diagnosis, therapeutic drug development, and preventive efforts, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality in the United States. Thus, new prevention strategies are urgently needed, especially for individuals with precancerous lesions or genetic predispositions, such those with familial adenomatous polyposis (FAP). ONC201 is a selective antagonist of dopamine receptor D2 that reduces cell proliferation and induces TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis via integrated stress response activation and AKT/ERK inactivation. It is highly specific for cancer cells, having no effect on normal cells at concentrations that inhibit cancer cell growth. ONC201 is orally available and has demonstrated a favorable safety profile in rats and dogs, as well as in Phase 1 trials in advanced solid tumors. In the Phase 1 trials, ONC201 was administered at doses up to 625 mg once weekly for 3 weeks. No drug-related toxicities greater than grade 1 were reported, and there were no treatment discontinuations or dose modifications due to drug-related toxicity. Some evidence of efficacy (stable disease) was also observed. ONC201 is currently being tested in several Phase 2 trials (e.g. NCT03034200, NCT03099499, NCT03295396, NCT03485729, NCT02525692, and NCT02420795). In terms of CRC, ONC201 has been shown to reduce the viability of HCT116 cells in vitro (6) and to inhibit the growth of HCT116 xenografts in vivo (5). In a recently completed PREVENT Task Order (https://projectreporter.nih.gov/project_info_description.cfm?aid=9360353&icde=50111042), ONC201, administered by gavage 2X/week at doses of 25 and 50 mg/kg, significantly reduced the incidence and multiplicity of colonic tumors, as well as the multiplicity of small intestinal tumors, in both male and female azoxymethane (AOM)-treated APCmin/+ mice without inducing any signs of toxicity. Non-steroidal anti-inflammatory drugs (NSAIDs) have also shown promise as CRC chemopreventive agents, although their long-term use is hindered by concerns for gastric and cardiac toxicity. For example, 200 and 400 ppm naproxen, administered in the diet, reduces the multiplicity of adenomas, non-invasive adenocarcinomas, and invasive carcinomas when administered to AOM-treated rats continuously or on an intermittent schedule (1 week on and 1 week off). Furthermore, sulindac synergistically induces apoptosis in a variety of colon cancer and adenoma cell lines and in FAP-derived ex-vivo adenoma segments when combined with recombinant human TRAIL. The purpose of this Task Order is to expand upon the above-mentioned studies by (a) investigating the chemopreventive activity of ONC201 in the polyposis in the rat colon (Pirc) model, which, in contrast to tne APCmin/+ mouse model, primarily develops colonic tumors and thus more closely recapitulates human FAP, and (b) testing the hypothesis that the combination of ONC201 with naproxen will lead to enhanced efficacy while reducing the toxicity of the NSAID.

尽管在早期诊断、治疗药物开发和预防工作方面取得了重大进展，结直肠癌 (CRC) 仍然是美国癌症相关死亡的第三大原因。因此，迫切需要新的预防策略，特别是对于患有癌前病变或遗传倾向的个体，例如患有家族性腺瘤性息肉病（FAP）的个体。 ONC201 是多巴胺受体 D2 的选择性拮抗剂，可通过整合应激反应激活和 AKT/ERK 失活来减少细胞增殖并诱导 TNF 相关凋亡诱导配体 (TRAIL) 介导的细胞凋亡。它对癌细胞具有高度特异性，在抑制癌细胞生长的浓度下对正常细胞没有影响。 ONC201 可口服，并在大鼠和狗中以及晚期实体瘤的 1 期试验中表现出良好的安全性。在 1 期试验中，ONC201 的给药剂量高达 625 毫克，每周一次，持续 3 周。没有报告大于 1 级的药物相关毒性，也没有因药物相关毒性而停止治疗或调整剂量。还观察到一些疗效证据（疾病稳定）。 ONC201目前正在多项2期试验中进行测试（例如NCT03034200、NCT03099499、NCT03295396、NCT03485729、NCT02525692和NCT02420795）。就 CRC 而言，ONC201 已被证明可在体外降低 HCT116 细胞的活力 (6)，并在体内抑制 HCT116 异种移植物的生长 (5)。在最近完成的预防任务令 (https://projectreporter.nih.gov/project_info_description.cfm?aid=9360353&icde=50111042) 中，ONC201 以 25 和 50 mg/kg 的剂量每周灌胃 2 次，显着降低了男性和女性结肠肿瘤以及小肠肿瘤的发病率和多样性氧化偶氮甲烷 (AOM) 处理的 APCmin/+ 小鼠没有诱导任何毒性迹象。非甾体类抗炎药 (NSAID) 也显示出作为 CRC 化学预防药物的前景，尽管其长期使用因胃和心脏毒性问题而受到阻碍。例如，在饮食中给予 200 和 400 ppm 萘普生，当连续或间歇性地（给药 1 周，停药 1 周）给予 AOM 治疗的大鼠时，可减少腺瘤、非浸润性腺癌和浸润性癌的复数性。。此外，当与重组人 TRAIL 组合时，舒林酸可协同诱导多种结肠癌和腺瘤细胞系以及 FAP 衍生的离体腺瘤片段的细胞凋亡。本任务顺序的目的是通过 (a) 研究 ONC201 在大鼠结肠息肉病 (Pirc) 模型中的化学预防活性，该模型与 APCmin/+ 小鼠模型相比，主要发展结肠肿瘤，从而更接近地再现人类 FAP，并且（b）测试 ONC201 与萘普生的组合将导致功效增强同时降低毒性的假设非甾体抗炎药。