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

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方面取得了重大进展,但结直肠癌(CRC)仍然是美国癌症相关死亡率的第三大原因。因此,迫切需要新的预防策略,特别是对于具有癌前病变或遗传易感性的个体,例如具有家族性腺瘤性息肉病(FAP)的个体。 ONC 201是多巴胺受体D2的选择性拮抗剂,其通过整合的应激反应激活和AKT/ERK失活来减少细胞增殖并诱导TNF相关的凋亡诱导配体(TRAIL)介导的凋亡。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。ONC 201可口服,在大鼠和犬中以及晚期实体瘤的I期试验中表现出良好的安全性。在1期试验中,ONC 201以高达625 mg的剂量每周一次给药,持续3周。未报告大于1级的药物相关毒性,也未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(病情稳定)。ONC 201目前正在几项II期试验中进行测试(例如NCT 03034200、NCT 03099499、NCT 03295396、NCT 03485729、NCT 02525692和NCT 02420795)。在CRC方面,已显示ONC 201在体外降低HCT 116细胞的活力(6)并在体内抑制HCT 116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),通过管饲法以25和50 mg/kg的剂量每周2次施用ONC 201,在雄性和雌性氧化偶氮甲烷(AOM)处理的APCmin/+小鼠中显著降低结肠肿瘤的发生率和多样性,以及小肠肿瘤的多样性,而不诱导任何毒性迹象。 非甾体抗炎药(NSAID)也显示出作为CRC化学预防剂的前景,尽管它们的长期使用受到胃和心脏毒性的影响。例如,在饮食中给予200和400 ppm的萘普生,当连续或以间歇时间表(给药1周和停药1周)给予AOM处理的大鼠时,可减少腺瘤、非侵袭性腺癌和侵袭性癌的多样性。此外,当与重组人TRAIL组合时,舒林酸协同诱导多种结肠癌和腺瘤细胞系以及FAP衍生的离体腺瘤区段中的细胞凋亡。 本任务指令的目的是通过以下方式扩展上述研究:(a)研究ONC 201在大鼠结肠息肉病(Pirc)模型中的化学预防活性,与APC min/+小鼠模型相比,Pirc模型主要发展结肠肿瘤,因此更接近于人类FAP,和(B)检验ONC 201与萘普生的组合将导致增强的功效同时降低NSAID的毒性的假设。

项目成果

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CHINTHALAPALLY RAO其他文献

CHINTHALAPALLY RAO的其他文献

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{{ truncateString('CHINTHALAPALLY RAO', 18)}}的其他基金

Base Title: PREVENT Preclinical Drug Development Program: Preclinical Efficacy and Intermediate Endpoint BiomarkersTask Order Title: Colorectal Cancer (CRC) Prevention by TPST-1495 in PIRC rat mod
基本标题:预防临床前药物开发计划:临床前功效和中间终点生物标志物任务顺序标题:TPST-1495 在 PIRC 大鼠模型中预防结直肠癌 (CRC)
  • 批准号:
    10927554
  • 财政年份:
    2023
  • 资助金额:
    $ 87.95万
  • 项目类别:
TITLE: BLADDER CANCER CHEMOPREVENTION USING THE ANDROGEN RECEPTOR INHIBITOR APALUTAMIDE
标题:使用雄激素受体抑制剂阿帕鲁胺进行膀胱癌化学预防
  • 批准号:
    10677989
  • 财政年份:
    2022
  • 资助金额:
    $ 87.95万
  • 项目类别:
TASK ORDER TITLE: PREVENTING LUNG ADENOCARCINOMA (LUAD) USING TRAIL INDUCING AGENT, ONC201BASE CONTRACT TITLE: PREVENT PRECLINICAL DRUG DEVELOPMENT
任务单标题:使用踪迹诱导剂预防肺腺癌 (LUAD),ONC201BASE 合同标题:预防临床前药物开发
  • 批准号:
    10705393
  • 财政年份:
    2022
  • 资助金额:
    $ 87.95万
  • 项目类别:
BASE TITLE: PREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKERSTASK ORDER TITLE: PREVENTING FAP-CRC USING
基本标题:预防临床前药物开发计划:临床前疗效和中间生物标志物订单标题:预防 FAP-CRC 使用
  • 批准号:
    10652736
  • 财政年份:
    2022
  • 资助金额:
    $ 87.95万
  • 项目类别:
PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM - A NOVEL MULTI-ANTIGEN VACCINE (TNBCVAX) TO PREVENT TRIPLE NEGATIVE BREAST CANCER
预防癌症临床前药物开发计划 - 预防三阴性乳腺癌的新型多抗原疫苗 (TNBCVAX)
  • 批准号:
    10503245
  • 财政年份:
    2021
  • 资助金额:
    $ 87.95万
  • 项目类别:
PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM - A NOVEL MULTI-ANTIGEN VACCINE (TNBCVAX) TO PREVENT TRIPLE NEGATIVE BREAST CANCER
预防癌症临床前药物开发计划 - 预防三阴性乳腺癌的新型多抗原疫苗 (TNBCVAX)
  • 批准号:
    10678625
  • 财政年份:
    2021
  • 资助金额:
    $ 87.95万
  • 项目类别:
PREVENT EFFICACY POOL: PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM
预防功效池:预防癌症临床前药物开发计划
  • 批准号:
    10411703
  • 财政年份:
    2021
  • 资助金额:
    $ 87.95万
  • 项目类别:
CHEMOPREVENTION WITH AEROSOLIZED LET-7 MICRORNA IN MOUSE MODELS OF NON-SMALL CELL LUNG CANCER (ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMA)
在非小细胞肺癌(腺癌和鳞状细胞癌)小鼠模型中使用雾化的 Let-7 微小RNA进行化学预防
  • 批准号:
    10020543
  • 财政年份:
    2019
  • 资助金额:
    $ 87.95万
  • 项目类别:
IGF::OT::IGF PROSTATE CANCER PREVENTION BY ASPIRIN AND/OR OTHER NSAIDS TORFP 2016-E03HHSN2612015000381PERIOD OF PERFORMANCE: 07/07/2016 - 03/06/2019
通过阿司匹林和/或其他非甾体抗炎药预防 IGF::OT::IGF 前列腺癌 TORFP 2016-E03HHSN2612015000381执行周期:07/07/2016 - 03/06/2019
  • 批准号:
    9360885
  • 财政年份:
    2016
  • 资助金额:
    $ 87.95万
  • 项目类别:
IGF::OT::IGF PREVENT EFFICACY: OPTIMIZATION OF GEM MODELS FOR HIGH-RISK COHORTS OF HUMAN PANCREATIC CYSTADENOMAS, IPMNS, AND PANINS PROGRESSION TO PDAC.
IGF::OT::IGF 预防功效:针对人类胰腺囊腺瘤、IPMNS 和 Panins 进展至 PDAC 高风险群体的 GEM 模型的优化。
  • 批准号:
    9152469
  • 财政年份:
    2015
  • 资助金额:
    $ 87.95万
  • 项目类别:

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腺瘤性大肠杆菌在预防结肠损伤和伤口愈合中的作用
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