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

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

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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.

尽管早期诊断，治疗性药物开发和预防性努力取得了重大进展，但大肠癌（CRC）仍然是美国与癌症相关死亡率的第三主要原因。因此，迫切需要新的预防策略，特别是对于患有癌性病变或遗传易感性的个体，例如患有家族性腺瘤性息肉病（FAP）的人。 ONC201是多巴胺受体D2的选择性拮抗剂，可减少细胞增殖并诱导与TNF相关的凋亡诱导配体（TRAIL）通过综合应激反应激活和AKT/ERK失活而介导的凋亡。它对癌细胞高度特异，在抑制癌细胞生长的浓度下对正常细胞没有影响。 ONC201可以口服，并且在大鼠和狗以及晚期实体瘤的第1阶段试验中表现出了良好的安全性。在第1阶段试验中，ONC201以每周625 mg的剂量施用3周。没有报道与药物有关的毒性大于1级的毒性，并且由于药物相关的毒性而没有治疗中断或剂量改性。还观察到了一些功效（稳定疾病）的证据。目前，ONC201在多个2期试验中进行了测试（例如NCT03034200，NCT03099499，NCT03295396，NCT03485729，NCT02525692，NCT02525692和NCT02420795）。在CRC方面，ONC201已被证明可以在体外降低HCT116细胞的活力（6），并抑制体内HCT116异种移植物的生长（5）。在最近完成的预防任务订单（https://projectReporter.nih.gov/project_info_description.cfm?aid=9360353&icde=50111042）中在男性和雌性甲氧基甲烷（AOM）处理的APCMIN/+小鼠中，小肠肿瘤的多样性，而无需诱导任何毒性迹象。非甾体类抗炎药（NSAID）也表现为CRC化学预防剂的希望，尽管其长期使用受到对胃和心脏毒性的担忧的阻碍。例如，在饮食中施用的200和400 ppm萘普生可以降低腺瘤，无创腺癌和侵入性癌的多样性，当时持续或间歇时间（1个星期的时间为1周）。此外，Sulindac协同诱导各种结肠癌和腺瘤细胞系的凋亡以及FAP衍生的前体内腺瘤段中的凋亡，与重组的人类步道结合使用。该任务顺序的目的是通过（a）研究大鼠结肠（PIRC）模型中ONC201的化学预防活性来扩展上述研究，该模型与TNE APCMIN/+小鼠模型相反，该模型与TNE APCMIN/+小鼠模型相反，主要开发了结肠肿瘤，并因此更加紧密地审查了人类FAP和（b）的作用。在降低NSAID的毒性的同时增强功效。