Emory University/Atlanta Veterans' Affairs Medical Center
Introduction: Androgen deprivation therapy (ADT) exerts immunomodulatory effects and induces a unique phenotypic response that accumulating data suggests may be improved with the addition of standard medications. Prior studies have shown that ADT and metformin or statins improves oncologic outcomes versus ADT alone. We hypothesize that these outcomes may be due to the effects of statins and ADT in immune and prostate tumor modulation. We aim to investigate whether Atorvastatin ± ADT alters tumor growth, proliferation, apoptosis and the immune infiltrate within myc-CaP/AS murine models. Methods: FVB/NJ, immunocompetent mice were injected subcutaneously with 1x106 Myc-CaP/AS cells. Treatment was initiated at an average tumor volume of 400mm3. Groups were randomized into short term (5 days post ADT) and long term (10 days post) for a total of 8 mice per group per time period. Mice were injected i.p. with: 1) 5µg/g Atorvastatin, q2 days x 3 doses OR q2 days x 5 doses AND/OR 2) Degarelix 25µg/g x 1 dose OR 3) PBS i.p. for controls. Immunohistochemical staining, followed by flow cytometry, was performed using single cell suspensions of harvested tumors. Western blots were performed to assess expression of PCNA and CC3. Results: ADT + Atorvastatin treated tumors had the greatest decrease in volume (Figure). Tumor volume differences were present between post-treatment Atorvastatin vs control (p=0.029) and post-treatment Degarelix +Atorvastatin vs control (p=0.018). On flow cytometric analysis, Atorvastatin-treated tumors had the greatest CD8 T-cell expansion over time. MDSC expression decreased significantly over time for ADT and ADT + Atorvastatin-treated tumors. Early ADT and ADT + Atorvastatin decreased tumor proliferation and late Atorvastatin increased apoptosis in myc-CaP/AS tumors. Conclusions: Atorvastatin + ADT combination therapy decreased tumor volume and tumor proliferation when compared to ADT or statin drug alone. Atorvastatin alone increased CD8 T-cell presence, important for cell death, and in combination with ADT, decreased MDSC expression, which impedes cancer cell death. Demonstrating synergy between androgen deprivation and immunomodulatory agents has to potential to shift the treatment paradigm in patients with high-risk prostate cancer. SOURCE OF Funding: AUA/UCF Grant# 017-822959
