Abstract 6336: Preclinical efficacy of TRAIL inducing ONC201 against carcinogen (NNK)-induced lung adenocarcinoma in A/J mouse model

Abstract Lung cancer is the 2nd most commonly diagnosed cancer in both genders in the US. Most lung tumors are diagnosed at late stages and distant metastasis drastically reduces 5-year survival to <10%. Hence, intercepting lung tumor progression would aid in reducing tumor burden and cancer mortality. Preclinical and TCGA data demonstrated that the TNF Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) is incrementally downregulated with lung tumor progression. Hence we evaluated ONC201 (Dordaviprone), a orally active TRAIL-inducing small molecule for its cancer preventive efficacy in the tobacco carcinogen Nicotine-derived Nitrosamine Ketone (NNK) driven A/J mouse lung cancer model. Prior to the efficacy studies, five different oral doses of ONC201 (0-200mg/kg BW) were tested in A/J mice (n=6/gender/group) for optimal dose range selection. For efficacy evaluation, A/J mice (6 weeks age; n=20/sex/group) were randomized into vehicle control and intervention groups; and lung tumors were induced by a single i.p. injection of NNK (2.07mg/mouse). Six-weeks after NNK injection, mice were given 0, 25, 50, or 100mg/kg BW ONC201 (in PBS) by oral gavage twice weekly for 28 weeks. Mice were then euthanized and lungs were evaluated for tumor incidence and multiplicity. All of the NNK-injected control mice developed lung tumors (100% incidence); but significant difference (p<0.001) was observed in tumor multiplicity between genders (17±2.18 in females (Mean±SEM) Vs 7.7±0.89 in males). ONC201 treatment led to significant decrease in tumor multiplicity at all 3 tested doses in both genders (25-43% less tumors; p<0.05-p<0.001). Lung tumors were classified as adenomas (AD), and adenocarcinomas (AdCa) based on histological criteria. Control mice developed 2.25±0.19 AD, and 5.45±0.69 AdCa in male; 3.89±0.57 AD, and 11±1.24 AdCa in female mice. While ONC201 treatment reduced the adenomas moderately, AdCa was significantly inhibited at all 3 doses in both genders in a dose dependent manner. In the female mice, AdCa multiplicity was reduced by 27% (p<0.05), 53% (p<0.001), and 70% (p<0.0001) in 25 mg/kg, 50 mg/kg, and 100 mg/kg BW ONC201 respectively. Similarly, AdCa was inhibited by 55% (p<0.001), 67% (p<0.0001), and 84% (p<0.0001) in male mice at the 3 dose levels as compared to controls. No toxicities were observed in all doses tested in both genders. Biomarker analysis of the lung tumors using IHC and Western blotting analysis suggested an induction of TRAIL signaling pathway markers, increased apoptosis, and a decrease in proliferation markers (PCNA, Cyclin D1, EGFR, Ki67). In conclusion, our data indicate a strong preventive efficacy of ONC201 in a preclinical model of lung cancer and warrant further development towards clinical applications for lung cancer prevention in high-risk cohorts. (Project funded 100% with Federal funds from NCI, NIH, DHHS, under Contract 75N91019D00020_75N91022F00003) Citation Format: Karthikkumar Venkatachalam, Venkateshwar Madka, Gopal Pathuri, Anil Singh, Anh Bao, Nicole Stratton, Shizuko Sei, Vignesh Gunasekharan, Chinthalapally V. Rao. Preclinical efficacy of TRAIL inducing ONC201 against carcinogen (NNK)-induced lung adenocarcinoma in A/J mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6336.