Abstract B012: Anti-tumor activity of the METAP2 inhibitor evexomostat (SDX-7320) in multiple stage-specific models of prostate cancer, including treatment refractory and neuroendocrine (AVPC) phenotypes

Abstract Background: Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARSIs is a significant clinical issue associated with aggressive variant prostate cancer (AVPC), and consequently there is an urgent need for novel, AR pathway-independent therapies. Expression of the metalloprotease methionine aminopeptidase 2 (METAP2) has been correlated with increased mCRPC aggressiveness: high expression was reported in dedifferentiated phenotypes, including NEPC/AVPC. METAP2 regulates protein translation, post-translational modifications and has a clinically validated role inhibiting angiogenesis. METAP2 also has tumor-specific functions coordinating plasticity, vascular mimicry, and hypoxia response. Evexomostat (SDX-7320) is a prodrug of a highly potent, novel METAP2 inhibitor which has completed a phase I safety study in late-stage cancer patients and is currently being clinically investigated in patients with metastatic breast cancer (NCT05570253, NCT05455619). It was hypothesized that SDX-7320 would demonstrate anti-tumor efficacy in non-clinical prostate cancer xenograft models of ARPI-resistant CRPC and AVPC. Methods: SDX-7320 was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35.CR patient-derived xenografts (PDX) in castrate mice as well as in combination with enzalutamide following development of resistance to daily enzalutamide treatment. SDX-7320 was further evaluated in the LTL545 and LUCAP49 (AR-negative, NE-positive) models of AVPC. Tumor growth was assessed and following dissection, subsequently analyzed for transcriptomic (RNAseq), protein (Western blot) or histological differences (H&E staining, CD34 IHC). Results: SDX-7320 treatment significantly reduced tumor volume in every model and at every PC stage investigated, as single agent and in combination with enzalutamide (in AR-resistant tumors), as well as in the AR-negative LTL545 and LUCAP49 models. Reduced CD34 staining was observed in all tumors from SDX-7320-treated mice. Gene and gene-set variation analysis of RNA-sequenced xenograft AR+ tumors identified significantly decreased expression of cell cycle-associated genes and upregulation of genes associated with hypoxia, apoptosis and inflammation. Furthermore SDX-7320 treatment increased expression of some AR target genes, suggesting a beneficial effect on tumor differentiation. Treatment with SDX-7320 also resulted in the down-regulation of MYC target genes as well as MYC protein in both AR-positive and AR-negative AVPC models along with decreases in neuroendocrine gene signatures. Additionally, EZH2 protein was decreased in both AR+ and in AVPC models treated with SDX-7320. Conclusions: These results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat therapy-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation. Citation Format: Peter Cornelius, Devina Laurencia, Jennifer H. Gunter, Anja Rockstroh, Benjamin A. Mayes, Pierre Dufour, Bradley J. Carver, James M. Shanahan, Colleen Nelson. Anti-tumor activity of the METAP2 inhibitor evexomostat (SDX-7320) in multiple stage-specific models of prostate cancer, including treatment refractory and neuroendocrine (AVPC) phenotypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B012.