Abstract B031: MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models
Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARPIs is a significant clinical issue associated with the emergence of 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 (NCT02743637) 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 cell-derived xenograft and patient-derived xenograft (PDX) models of ARPI-resistant CRPC and AVPC. SDX-7320 (12 or 8 mg/kg, subcutaneous dosing, every four days) was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35.CR PDX xenografts in castrate mice alone as well as in combination with enzalutamide following development of resistance to enzalutamide. SDX-7320 was also tested in the LTL545, LUCAP49 and LTL331R (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). SDX-7320 treatment significantly reduced tumor volume in every model and at every PC stage investigated, alone and in combination with enzalutamide (in enzalutamide-resistant tumors), as well as in the LTL545, LUCAP49 and LTL331R AVPC models. Reduced angiogenesis marker CD34 staining was observed in all tumors from SDX-7320-treated mice. Survival of mice treated with SDX-7320 was significantly enhanced, regardless of model phenotype. Downstream analyses of bulk RNAseq and proteomics showed model-specific changes to plasticity regulators c-Myc and the enhancer of zeste homolog 2 (EZH2) indicating an effect of METAP2 inhibition on prostate cancer cellular differentiation. These results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat ARPI-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation. Building upon the non-clinical data in models of AVPC presented here, combined with the body of clinical experience with SDX-7320 in past and ongoing clinical trials, planning is underway to conduct a pilot clinical trial with SDX-7320 in men with AVPC. Peter Cornelius, Devina Laurencia, Jennifer H. Gunter, Anja Rockstroh, Benjamin A. Mayes, Pierre Dufour, Bradley J. Carver, James M. Shanahan, Colleen C. Nelson. MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B031.