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
• 负责人: CHINTHALAPALLY RAO
• 金额: $ 98.23万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2025-09-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705393
• 关键词: A549; Adenocarcinoma Cell; Apoptosis; Biological Markers; Body Weight; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Canis familiaris; Cell Proliferation; Chemicals; Clinical; Contracts; Dopamine Antagonists; Dopamine D2 Receptor; Dose; Drug Kinetics; Epidermal Growth Factor Receptor; Genes; Genetically Engineered Mouse; Hyperplasia; Individual; KRAS2 gene; Lung Adenocarcinoma; Lung Neoplasms; Lung nodule; Malignant neoplasm of lung; Mediating; Modeling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Normal Cell; Oral; Pharmaceutical Preparations; Pharmacodynamics; Pre-Clinical Model; Preclinical Drug Development; Prevention strategy; Preventive; Property; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Reporting; SCID Mice; Safety; Sampling; Schedule; Signal Transduction; Solid Neoplasm; Squamous cell carcinoma; Survival Rate; TNF-related apoptosis-inducing ligand; TNFRSF10B gene; Testing; Toxic effect; Xenograft procedure; adenoma; biological adaptation to stress; cancer cell; high risk; lung small cell carcinoma; mortality; mouse model; mutant; phase I trial; phase II trial; prevent; smoking cessation; tumor growth

Lung cancer is the leading cause of cancer mortality in the US and worldwide. Of the two main histopathological types of lung cancer, non-small cell lung cancer (NSCLC) - which includes adenocarcinoma (AC) and squamous cell carcinoma (SCC) - comprises approximately 85% of all lung cancer patients while small cell lung cancer (SCLC) makes up the remaining 15%. KRAS mutations are found in ~25% of lung adenocarcinomas (LUADs), EGFR mutations are seen in ~15% of LUADs, and the remaining are small percentages of other mutations. At present, the 5-year survival rate of lung cancer is <20%, thus, underscoring preventive strategies including smoking cessation and secondary preventive approaches for high-risk individuals with atypical lung nodules with hyperplasia and adenomas. ONC201 (TIC10) 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, the dose was well tolerated, and displayed favorable pharmacokinetic properties in trial subjects. ONC201 is currently being tested in several Phase 2 trials (e.g., NCT03034200, NCT03295396, NCT03485729, NCT02525692, and NCT04055649). Preliminary studies with ONC201 have shown that ONC201 suppresses the lung tumor growth of A549 xenografts in SCID mice in a dose-dependent manner. Both the tested doses (10 and 50 mg/kg ONC201) did not affect the body weights of treated mice and significantly increased TRAIL and Death Receptor 5 (DR5) protein levels while inactivating Akt- Erk signaling. The purpose of this Task Order is to determine the potential clinical usefulness of ONC201 in preventing high risk LUAD in preclinical models.

肺癌是美国和世界范围内癌症死亡的主要原因。在肺癌的两种主要组织病理学类型中，非小细胞肺癌(NSCLC)--包括腺癌(AC)和鳞状细胞癌(SCC)--约占所有肺癌患者的85%，而小细胞肺癌(SCLC)占其余15%。KRAS突变见于约25%的肺腺癌(LUAD)，EGFR突变见于约15%的LUAD，其余为少量其他突变。目前，肺癌的5年生存率为20%，因此强调了预防策略，包括戒烟和针对患有非典型肺结节并伴有增生和腺瘤的高危个体的二级预防方法。 ONC201(TIC10)是多巴胺D2受体的选择性拮抗剂，通过整合应激反应激活和AKT/ERK失活，抑制细胞增殖，诱导肿瘤坏死因子相关的凋亡诱导配体(TRAIL)介导的细胞凋亡。它对癌细胞有高度的特异性，在抑制癌细胞生长的浓度下对正常细胞没有影响。ONC201可口服使用，并已在大鼠和狗身上显示出良好的安全性，以及在晚期实体肿瘤的第一阶段试验中。在第一阶段试验中，ONC201的剂量最高为625毫克，每周一次，持续3周。没有报告与药物相关的毒性超过1级，该剂量耐受性良好，并在试验受试者中表现出良好的药代动力学特性。ONC201目前正在进行几个第二阶段试验(例如，NCT03034200、NCT03295396、NCT03485729、NCT02525692和NCT04055649)。对ONC201的初步研究表明，ONC201以剂量依赖的方式抑制SCID小鼠A549移植瘤的生长。受试剂量(10和50 mg/kg ONC201)均不影响受试小鼠的体重，并显著增加TRAIL和死亡受体5(DR5)的蛋白水平，同时抑制Akt-Erk信号转导。该任务顺序的目的是确定ONC201在临床前模型中预防高危LUAD的潜在临床有用性。