Abstract 6 UT MD Anderson Cancer Ctr., Houston, TX.Prostate cancer (PCa) progression remains a major clinical challenge with limited therapeutic options, and the complexity of metabolic pathways fueling advanced PCa rests poorly understood. We have identified a shift from glycolysis to ketone body (KB) metabolism in castration-resistant PCa (CRPC), with an upregulation of ketolytic/ketogenic enzymes. From these, ACAT1 is a potential therapeutic candidate, as its expression is elevated in aggressive PCa and associates with unfavorable clinical outcomes. Here, we investigated the contribution of the bone niche -the dominant PCa metastatic site- to KB metabolism during PCa progression and evaluated ACAT1 inhibition as a treatment strategy for advanced disease. Co-culture experiments between PCa cells and bone progenitors (MC3T3, Raw264.7) were used to evaluate bone-driven metabolic adaptations. To validate in vivo the effect of the bone niche, we implanted MDA PCa patient-derived xenograft (PDX) 183 either intrafemorally (i.f.) or subcutaneously (s.c.) in sham or castrated CB17 SCID mice. We assessed cell viability in PCa cells lines and in PDX-derived organoids (PDX.DO), treated with increasing concentrations of ACAT1 inhibitor, arecoline hydrobromide (AH). ACAT1 and phospho-ACAT1 levels were measured by Western blot and immunofluorescence. Intracellular KB and ATP content were quantified by luciferase-based assays. Lipid uptake and accumulation were quantified by flow cytometry using Bodipy probes. In vivo, mice bearing MDA PCa PDXs 183, 203 and 173 were treated with AH (50 mg/kg/day i.p., 21 days). Tumor volume, KB content, and ACAT1 modulation were evaluated. We observed transcriptional activation of lipid and KB metabolism in PC3 cells from PCa-bone co-cultures, and consistently, in i.f. PDXs compared to matched s.c. tumors, alongside a significant increase in ACAT1 expression levels. Castration dynamically modulated ACAT1 levels in MDA PCa 183 tumors growing i.f., with initial downregulation followed by restoration over time, underscoring KB metabolism as a mechanism of resistance within the bone niche. Functional studies showed that AH treatment reduced cell viability in PC3, C42B, and 22Rv1 cells, as well as PDX.DO, decreased ACAT1 and phospho-ACAT1 expression, lowered KB levels, and altered lipid dynamics by increasing lipid accumulation, uptake, and decreasing ATP content (P0.05). In vivo, AH treatment in MDA PCa 183 tumors led to a significant reduction in tumor volume and intratumoral KB content (P0.05). Moreover, in the CRPC model MDA PCa 203 -derived from a longitudinal sample of the same patient as 183-, and in the aggressive hormone-naïve model MDA PCa 173, AH treatment significantly reduced both tumor volume and KB content (P0.05). In conclusion, our findings reveal KB metabolism as a critical vulnerability in PCa progression, with ACAT1 emerging as a druggable target whose inhibition disrupts tumor growth and metabolic fitness. Citation Format: Pablo Sanchis, Agustina Ayelen Sabater, Jiabin Dong, Peter Shepherd, Nicolás Anselmino, Paul G. Corn, Elba Vazquez, Christopher J. Logothetis, Daniel Frigo, Geraldine Gueron, Estefania Labanca. Exploiting ketone body metabolism as a therapeutic vulnerability in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4740.
Sanchis et al. (2026) studied this question.