Exploiting ketone body metabolism as a therapeutic vulnerability in prostate cancer
Presenter: Pablo Sanchis, BS;PhD Session: Metabolic Features of Thoracic and Urologic Cancers Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Pablo Sanchis 1 , Agustina Ayelen Sabater 2 , Jiabin Dong 3 , Peter Shepherd 3 , Nicolás Anselmino 4 , Paul G. Corn 3 , Elba Vazquez 5 , Christopher J. Logothetis 6 , Daniel Frigo 3 , Geraldine Gueron 5 , Estefania Labanca 7 1 UT MD Anderson Cancer Center, Houston, TX, USA; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica (IQUIBICEN), Argentina; Universidad Argentina de la Empresa (UADE), Instituto de Tecnología (INTEC), Buenos Aires, Argentina, 2 UT MD Anderson Cancer Center; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica (IQUIBICEN), Argentina; Universidad Argentina de la Empresa (UADE), Instituto de Tecnología (INTEC), Buenos Aires, Argentina, Houston, TX, 3 UT MD Anderson Cancer Center, Houston, TX, 4 University of Buenos Aires, CABA, Argentina, 5 University of Buenos Aires, Buenos Aires, Argentina, 6 Chairman/Professor, Gu Med. Onc., UT MD Anderson Cancer Center, Houston, TX, 7 UT MD Anderson Cancer Ctr., Houston, TX
Abstract
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 (P In vivo , AH treatment in MDA PCa 183 tumors led to a significant reduction in tumor volume and intratumoral KB content (P<0.05). 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 (P<0.05). 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.
Disclosure
P. Sanchis, None.. A. A. Sabater, None.. J. Dong, None.. P. Shepherd, None.. N. Anselmino, None.. P. G. Corn, None.. E. Vazquez, None.. C. J. Logothetis, None.. D. Frigo, None.. G. Gueron, None.. E. Labanca, None.
Cited in
Control: 6636 · Presentation Id: 9172 · Meeting 21436