Abstract 4239: Alternate-day fasting enhances the activity of anti-androgen therapy in prostate cancer models
Authors: Cordova Ricardo , Elbanna May , Klunk Angela , Rupert Christopher , Shen Li , Wang Yanqing , Goodrich David , Wek Ron , Staschke Kirk , Fontana Luigi , Pili Roberto 
Published: April 2023

Abstract
Prostate cancer (PCa) is the most common cancer diagnosed in men in the Western countries. Epidemiological studies have suggested that environmental factors such as the Western diet, characterized by the consumption of high caloric food containing large amounts of animal protein and fats, play a key role in the pathogenesis of PCa. We propose that dietary intervention, by reducing caloric or protein intake, may be beneficial for the treatment of PCa. Our previous data suggests that dietary protein restriction reduces tumor growth in a LuCaP23.1 patient-derived xenograft (PDX) model of PCa. Thus, we tested the hypothesis whether caloric restriction induced by alternate-day fasting has a similar effect. Interestingly, caloric restriction had antitumor activity in the LuCaP23.1 model but only alternate-day fasting reduced the expression of androgen receptor (AR), a major driver of PCa growth. Therapies targeting AR activity, termed androgen deprivation therapies including the AR antagonist enzalutamide (ENZ), are the current standard of care for PCa. To address the therapeutic potential of combining alternate-day fasting with anti-androgens, we utilized the syngeneic mouse PCa xenograft models MyC-CaP and PTEN−/− RB−/−, and the human LuCaP23.1 PDX model. These AR-positive xenograft models harbor the oncogenic drivers most frequently found in PCa (i.e., MYC amplification and loss of the tumor suppressor PTEN). Here, we show that alternate-day fasting enhances the activity of ENZ in these PCa xenograft models. Interestingly, the combination of alternate-day fasting with ENZ treatment reduced AR expression and signaling, and decreased proliferation and tumor growth as compared to either single treatment alone. Consistent with these findings, the reduction of AR activity by the depletion of endogenous androgens following surgical castration was enhanced with alternate-day fasting. Conversely, dietary protein restriction had no effect in combination ENZ in vivo, suggesting that modulation of AR by alternate-day fasting enhances the effect of anti-androgens. Transcriptomic analysis of tumors from fasted mice confirmed decreased AR transcriptional activity and revealed that several nutrient sensitive pathways were reduced by this dietary regimen, including PI3K/AKT signaling, mTORC1 signaling, and glycolysis. Additionally, we observed that several known factors induced by fasting were upregulated in tumors from fasted mice, including SIRT1 which has been suggested to modulate AR transcriptional activity. In conclusion, we demonstrate that alternate-day fasting reduces AR signaling and enhances the activity of ENZ in several PCa xenograft models. Overall, this study suggests that caloric restriction may improve the efficacy of anti-androgen therapy in PCa patients.
Citation Format: Ricardo Cordova, May Elbanna, Angela Klunk, Christopher Rupert, Li Shen, Yanqing Wang, David Goodrich, Ron Wek, Kirk Staschke, Luigi Fontana, Roberto Pili. Alternate-day fasting enhances the activity of anti-androgen therapy in prostate cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4239.