Abstract 1483: Lipid oxidation via CPT1 as a target for prostate cancer imaging and therapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Prostate cancer (PCa) is the most common cancer in males and is currently treated medically with androgen deprivation therapy. However, resistance to androgen receptor (AR) targeted therapy develops in almost all patients over time. Simultaneously targeting multiples pathways may prevent the development of this resistance. Recent studies suggest PCa relies on lipid fuel over glycolysis. Blocking the ability of PCa to use lipids inhibits its growth and leads to apoptosis but enhances glucose uptake initially, potentially enhancing glucose-based FDG-PET (18F-dexyglucose-Positron Emission Tomography) imaging of PCa tumors. Experimental approach: To address the role of lipid metabolism in PCa we have used etomoxir, a clinically utilized drug that blocks lipid oxidation by inhibiting carnitine palmitoyltransferase (CPT1) in the mitochondria. Enzalutamide is a clinically available anti-androgen, which was used by itself or in combination with etomoxir. The gene/drug interaction was studied in LNCaP cells with decreased expression of CPT1A (via shRNA). PET-FDG of mouse xenografts were used to evaluated the glycolytic switch induced by systemic etomoxir treatment in 24 hours and the therapeutic effect over time. Results: Treatment with etomoxir alone significantly decreased cell viability and AR content, including ARv7 variant. Combinatorial treatment with enzalutamide synergistically enhanced this effect on viability. CPT1A Knockdown clones were also more sensitive to enzalutamide (2 fold, p<0.001) compared to control clones, and this effect was associated with reduced AR expression. Systemic treatment with etomoxir alone in nude mice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease PCa tumor growth. Interestingly, FDG uptake by VCaP xenografts was increased with systemic etomoxir in 24 hours (∼1.5 fold, P<0.05), enhancing the visualization of the tumors in the PET scans. FDG uptake in the mouse non-cancerous prostate tissue was negligible with etomoxir. Conclusions: Safely blocking lipid oxidation in PCa results in decreased viability with temporarily increased glucose uptake, due to a flare of glucose uptake to compensate for the fat oxidation blockade. Validation in human PCa patients with localized disease is needed to confirm these preclinical studies. Additionally, the decreased viability over time suggests that lipid metabolism is needed to maintain AR expression and combination of fat burning inhibitors and enzalutamide may offer novel approach to anti-AR resistance in PCa. Citation Format: Isabel R. Schlaepfer, Maren Salzmann-Sullivan, Lih-Jen Su, L.Michael Glode, Thomas Flaig. Lipid oxidation via CPT1 as a target for prostate cancer imaging and therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1483. doi:10.1158/1538-7445.AM2015-1483