Abstract 3110: A clinically actionable lipid metabolic approach in potentiating the response to anti-androgen therapy in a castration resistant prostate cancer model

Abstract Purpose: Despite better management of prostate cancer (PCa) and good response rates to androgen deprivation therapies (ADT), patients that progress towards metastatic disease remain refractory to therapy with poor prognosis. There is a significant unmet need in sensitizing castrate-resistant PCa (CRPC) to agents such as enzalutamide (ENZ). A significant body of literature has shown saturated fatty acids (SFA) and mono-unsaturated fatty acids (MUFA) protect cancer cells from the deleterious effects of reactive oxygen species (ROS), and conversely, membrane poly-unsaturated fatty acids (PUFA) promote it. Considering that PCa is driven by androgen signaling, and that AR is upstream of lipogenesis and therefore SFA and MUFA production, we aimed to develop a pharmacological approach to sensitize CRPC to treatment, using a combination of the fatty acid synthase (FASN) inhibitor TVB-3664, enzalutamide (ENZ), and the ROS inducer arsenic trioxide (ATO). Experimental Design: We treated castration sensitive (CS) and CRPC cell lines with combinations of TVB, ENZ and ATO and recorded live and dead cell counts. We then tested these treatments in vivo on a therapy resistant patient derived xenograft, LuCaP35 CR. We used a phospholipidomics approach to evaluate the effect of these treatments individually and in combination on membrane lipid profiles of the LuCaP35CR tumors. Results: CS cell lines were sensitive to single agent treatments with ENZ (p<0.0001), ATO (p<0.0001) and TVB (p<0.01 to p<0.0001); combination therapies also reduced cell proliferation significantly (all p<0.0001). CR lines were resistant to ENZ but responded to TVB (p<0.0001) and ATO treatments (p<0.0001); combined treatments also reduced the number of live cells (all p<0.0001). In the pre-clinical LuCaP35CR model, TVB exposure led to a sensitization to ENZ, which was augmented by further exposure to ATO. The triple combination kept tumors at the baseline volume throughout treatment (p<0.0001). Phospholipidomics demonstrated that TVB directed FASN inhibition, alone and in combination with ENZ and ATO, led to a significant decrease in membrane MUFA (p<0.0001) and a significant increase in membrane PUFA (p<0.0001). In addition, there was a significant decrease in AR expression in the ENZ+TVB treated tumors compared to control (p<0.0001), ENZ alone (p<0.001), or TVB alone (p<0.0001). Conclusions: We adopted a therapeutic strategy in rendering CRPC ROS sensitive. Specifically, we used the FASN inhibitor TVB-3664 to elevate membrane PUFA, together with ENZ and the ROS elevating drug ATO. Critically, this clinically actionable combination therapy dramatically decreased the growth of pre-clinical cell lines and PDX models. Our results demonstrate the applicability and potential of a ROS sensitizing strategy in the treatment of CRPC. Citation Format: Cynthia Sprenger, Silvia Rodrigues, Ali Talebi, Kathryn Soriano Epilepsia, Shihua Sun, Caroline Fidalgo Ribeiro, Fabio Socciarelli, Jonas Dehairs, Lisa Butler, Johannes V. Swinnen, Massimo Loda, Stephen Plymate. A clinically actionable lipid metabolic approach in potentiating the response to anti-androgen therapy in a castration resistant prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3110.