Abstract 108P
Background
PC exhibits altered lipid metabolism, with elevated expression of Fatty Acid Synthese (FASN) enzyme, the rate-limiting step of de novo lipogenesis. FASN leads to the synthesis of saturated and monounsaturated fatty acids, crucial for fueling cancer cell growth. AR activates sterol response element-binding proteins (SREBPs), transcription factors that regulate lipid synthesis enzymes, including FASN. Preliminary data show that pharmacologic FASN inhibition decreases AR expression and its splice variant AR-V7. We hypothesize that combining FASN inhibition with AR-targeted therapy, specifically enzalutamide (Enza), could enhance CRPC antitumor activity. Pre-clinical data led to the design of a phase I clinical trial to evaluate TVB-2640 combined with Enza as a new treatment approach for mCRPC.
Methods
PC cells (22Rv1 and LNCaP-95 with and without lentiviral-mediated overexpression of AR-V7) and MSK-PCa3 organoids were treated with FASN inhibitor (TVB-2640), Enza, or the combination. Cell growth and AR/AR-V7 expression were measured after treatment. LuCap 35 castrate-resistant PDXs were implanted into 12 castrated SCID mice and treated with Enza, TVB-2640, or the combination. Tumor growth was measured after treatment. FASN, AR, and AR-V7 expression was analyzed in metastatic tissue samples from mCRPC pts using immunohistochemistry (IHC).
Results
Combining the FASN inhibitor with Enza significantly inhibited cell growth compared to either drug alone in PC cells and CRPC organoids. The combination downregulated AR-V7 and FASN. The overexpression of AR-V7 in LNCaP-95 cells partially rescued cell growth inhibition. The drug combination also demonstrated a significant reduction in tumor growth compared to either drug alone in LuCap 35 PDX tumors. Multiplexed fluorescent IHC analysis of 55 mCRPC cases showed co-expression of FASN with AR (87%) and AR-V7 (39%) in metastatic PC lesions. A phase I clinical trial has commenced aimed at determining the optimal and safest dose of TVB-2640 combined with Enza in mCRPC pts.
Conclusions
De novo lipid synthesis inhibitors in combination with AR-targeted therapy is a promising new approach to treating mCRPC.
Clinical trial identification
NCT0574362.
Editorial acknowledgement
Legal entity responsible for the study
David Nanus, Weill Cornell Medicine, New York, NY, USA.
Funding
This work was supported in part by National Cancer Institute grants: prostate cancer SPORE P50CA211024 and WCM Prostate Cancer SPORE’s Developmental Research Program Award, P01 CA265768, the Prostate Cancer Foundation 2022CHAL05, the DoD W81XWH-19-1-0566.
Disclosure
All authors have declared no conflicts of interest.