Abstract PR007: Precision nutrition potentiates radiotherapy in prostate cancer

Abstract Background: While curative treatment is achievable for localized prostate cancer (PCa), radiotherapy often fails, with recurrence rates of 20-50%, highlighting need for strategies to improve efficacy and reduce disease progression. Chronic high-saturated fat intake (SFI) accelerates PCa progression but also creates metabolic vulnerabilities, such as obesity-driven tumor glycolysis, that may be exploited. Transiently harnessing and targeting these vulnerabilities through precision nutrition could represent a breakthrough approach. Methods: We investigated chronic and short-term SFI impact on radiotherapy response using the Hi-MYC genetically engineered mouse model, MyC-CaP and TRAMP-C2 murine PCa cell lines, and LuCaP castration-resistant PCa (CRPC) PDX models. Experiments used immunocompetent (FVB, C57BL/6N) and immunodeficient (CB17 SCID, NOD SCID) strains. Clinical relevance was assessed in patient cohort from the Health Professionals Follow-up Study (HPFS) with detailed dietary intake and clinical outcomes. Results: In Hi-MYC prostates, chronic SFI induced a DNA damage response at the transcriptional level and elevated γH2A.X levels compared to control diet (CTD)-fed mice. Critically, short-term SFI (sSFI) was sufficient to induce DNA damage in MyC-CaP tumors allografted into FVB mice. To assess radiosensitization, MyC-CaP tumors grown in immunocompetent mice underwent 10-day sSFI plus radiotherapy, yielding markedly improved responses versus CTD-fed mice. This effect was confirmed using TRAMP-C2 syngeneic model, demonstrating that sSFI-enhanced radiotherapy efficacy is independent of MYC expression and mouse strain. In contrast, sSFI did not enhance radiotherapy efficacy in 15 LuCaP CRPC PDX models grown in immunodeficient CB17 SCID hosts. To determine immune dependency, we repeated the experiments with MyC-CaP and TRAMP-C2 cells in CB17 and NOD SCID mice. Notably, sSFI-mediated radiosensitization was lost in immunodeficient hosts. Immune profiling in FVB mice showed sSFI primed immunity for radiotherapy and reshaped the tumor microenvironment post-treatment. We further examined post-diagnostic fat intake and survival in 3,959 patients with stage T1–T3 PCa from the HPFS with a median follow-up for mortality of 12.8 years. Among those treated with radiotherapy (n = 1,765), replacing 10% of energy intake from carbohydrates with saturated fat was associated with a 34% reduction in PCa-specific mortality (N events 185, Hazard Ratio 0.66, 95% Confidence Interval 0.42–1.04), trending toward statistical significance (p = 0.07; replacement model). No association was observed for cancer-specific mortality in patients undergoing radical prostatectomy (n = 2,194). Conclusion: Our findings demonstrate that sSFI enhances radiotherapy efficacy in preclinical PCa models with an intact immune system and shows translational relevance in clinical cohort. Altogether, precision nutrition (i.e., tailoring diet to treatment modality) may optimize therapeutic outcomes in PCa. Citation Format: Walaa Alahmadi, Tianrui Xu, Maria Celia Fernandez, Yiwen Zhang, Megan Shanahan, Léa Bourguignon, Anna de Polo, Nadia Boufaied, Jiachen Ji, Paolo Chetta, Feryel Azzi, Isabelle Clément, Conner J. Sessions, Holly M. Nguyen, Giorgia Zadra, Francis Rodier, Dominique Trudel, Eva Corey, Julianna Blagih, Edward L. Giovannucci, Lorelei A. Mucci, David P. Labbé. Precision nutrition potentiates radiotherapy in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR007.