10.3389/fpsyg.2012.00132

Vollständiger Abstract

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<h4>Introduction</h4>Intravesical interferon-alpha (IFNα) gene therapy is approved by the FDA for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Identifying resistance mechanisms and deploying targeted combination treatment strategies is a rational approach to improving treatment responses. We identified the ErbB pathway as a resistance mechanism to IFNα gene therapy, and we hypothesized that combination treatment with an ErbB pathway blocker and IFN-α could improve outcomes in resistant tumors.<h4>Methods</h4>Murine bladder cancer cells were treated <i>in vitro</i> with lentiviral IFNα (LV-IFNα) gene therapy, with/without afatinib (Afa), a pan-ErbB inhibitor, and cell viability and migration assays were performed. <i>In vivo</i> studies were conducted in a syngeneic MB49 orthotopic murine bladder cancer model, and mice were randomized into five treatment groups and treated with single treatments: Ctrl (vehicle), LV-Ctrl, LV-IFNα, and combination treatments with LV-Ctrl/Afa or LV-IFNα/Afa.<h4>Results</h4>Combination therapy with LV-IFNα/Afa significantly reduced MB49 cell viability <i>in vitro</i> compared to all other treatment conditions. This additive effect on cell viability appeared to be driven by a combination of early-cytostatic and late-cytolytic effects. The combination treatment also markedly inhibited cell migration. Finally, the <i>in vivo</i> studies demonstrated improved overall survival (OS) with LV-IFNα/Afa (median OS was 49 days in the LV-IFNα/Afa group vs. 15, 14, 29, and 26 days in Ctrl, LV-Ctrl, LV-IFNα, and LV-Ctrl/Afa groups, respectively; log-rank <i>p</i> < 0.001).<h4>Conclusion</h4>Our findings suggest that the ErbB pathway may serve as a clinically actionable resistance mechanism to intravesical IFNα gene therapy and, when targeted concurrently, it may improve treatment efficacy.

Abstract: PubMed · Datensatz