Molecular Characterization Of Response To Interferon Alpha In Sensitive And Resistant Bladder Cancer Models

Background: Over 70% of patients newly diagnosed with bladder cancer will present with non-muscle invasive disease (NMIBC). The standard of care treatment to prevent recurrence and progression is tumor resection followed by Bacillus Calmette-Guerin (BCG). While this treatment regimen is effective for many patients, a significant fraction become resistant over time. Adenoviral-delivered IFNα gene therapy is emerging as a safe and efficacious treatment for BCG-refractory NMIBC. IFNα is a type 1 interferon that mediates complex tumor-immune interactions, and also has direct cytotoxic effect on tumors. While the mechanisms of IFNα have been extensively studied, it is unclear which of these mechanisms are most relevant for driving therapeutic response. It is also poorly understood why some tumors are sensitive to the direct cytotoxic effects of IFNα and others are resistant. Methods: Here, we investigate the molecular mechanisms of tumor-intrinsic sensitivity and resistance to IFNα. We characterized response of a panel of bladder cancer cell lines to treatment with IFNα, and performed concomitant gene expression profiling to identify molecular features and pathways associated with response and sensitivity. These features were then compared across responsive and non-responsive cancer cell line models from other tissues of origin including skin, pancreas, liver and lung. Results/Conclusions: Several bladder cancer models exhibited a dose-dependent cytotoxic response to IFNα treatments, while others were resistant to these effects. Genomic and mRNA features associated with IFNα sensitivity/resistance were identified. Pan-cancer cell line analysis identified conserved and putative tissue-specific differences in IFNα downstream signaling genes in resistant vs sensitive cell lines. These features are being evaluated and will inform future investigation of the mechanism of IFNα anti-tumor activity in patients. Citation Format: Robin Osterhout, Jennifer Green, Scott McDonnell, Amy Klova, Adeela Kamal. Molecular characterization of response to interferon alpha in sensitive and resistant bladder cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5857.