Anti-Androgen Therapy Radiosensitizes Androgen Receptor Positive Cancers to F-18 Fluorodeoxyglucose

Abstract

Background: A subset (35%) of triple negative breast cancers (TNBC) express androgen receptor (AR) activity. However, clinical trials with anti-androgen drugs have shown limited efficacy with about a 19% clinical benefit rate. We investigate the therapeutic enhancement of anti-androgens as radiosensitizers in combination with ¹⁸F-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) in TNBC. Methods: We screened five candidate drugs to evaluate shared toxicity when combined with either ¹⁸F-FDG, X-ray or ultraviolet (UV) radiation, at doses below their respective sub-IC50 values. Cytotoxic enhancement of anti-androgen in combination with ¹⁸F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Results: Bicalutamide (Bical), an anti-androgen drug, was identified to share similar toxicity in combination with either ¹⁸F-FDG or X-rays, indicating its sensitivity as a radiosensitizer to ¹⁸F-FDG. Cell proliferation assays demonstrated selective toxicity of combination Bical-¹⁸F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation induced damage to cells suggesting the role of Bical as a radiosensitizer to ¹⁸F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1 and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of Bical and ¹⁸F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathology corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. Conclusion: These data provide evidence that ¹⁸F-FDG in conjunction with anti-androgens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.