A novel LSD1 inhibitor Seclidemstat as a promising candidate for the treatment of prostate cancer

HAN, RUOLAN; VAZQUEZ, RAMIRO; RIVEIRO, MARÍA EUGENIA; REZAI, KEYVAN; HUGUET, SAMUEL; BREKRADDA, MOHAMED; CATAPANO, CARLO V.; JIMÉNEZ, BÁRBARA; LARSON, JEFFERY L.; SOLDI, RAFFAELLA

Austin

Conferencia; INNOVATIONS IN CANCER PREVENTION AND RESEARCH CONFERENCE V; 2017

Cancer Prevention and Research Institute of Texas

Introduction: Lysine-specific demethylase 1 (LSD1) overexpression correlates with disease progression and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling. We examined the antitumor efficacy of LSD1 inhibition with Seclidemstat (SP-2577), a novel small molecule reversible inhibitor of LSD1 in several models of advanced-stage prostate cancer with various status of androgen receptor (AR) expression. Methods: A panel of prostate cancer cell lines with various AR status -DU145 and PC3 (AR-), LNCaP (AR-FL), 22RV1 and VCaP (AR-FL and AR-SV7)- and the normal prostate epithelial cell line RWPE-1, were used to examine the cell survival, colony formation, histone methylation, LSD1 expression, LSD1 and AR interaction upon treatment with Seclidemstat. Single-agent in vivo efficacy was examined in 22RV1 xenograft in nude mice in comparison with docetaxel. In vitro combination studies, using Seclidemstat with docetaxel or enzalutamide, were performed to assess the synergy. (AR-FL: full-length androgen receptor; AR-SV7: androgen receptor splice variant 7) Results: Seclidemstat potently inhibits the growth of all 5 prostate cancer cell lines tested regardless of AR status, while it has no effect in the proliferation of RWPE-1 cells. Seclidemstat also inhibits the colony formation of DU145, 22RV1and LNCap cells. Seclidemstat treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels and a decrease in LSD1 expression in both LNCap and PC3 cells. Seclidemstat treatment also caused a decrease of the LSD1-AR interaction in LNCap cells. Orally-administered Seclidemstat significantly reduced the tumor growth of 22RV1 xenografts in mice comparable to that of docetaxel with no apparent toxicity. Seclidemstat potentiated the anti-proliferative effect of enzalutamide in AR+ prostate cancer cell lines, whereas it is synergistic with docetaxel in both AR+ and AR- cell lines. Conclusions: LSD1 inhibition with Seclidemstat shows potent antitumor activity in vitro in both androgen-dependent and independent cell lines and inhibits tumor growth of castration-resistant 22RV1 xenograft in vivo. Seclidemstat also shows promise in combination therapy with standard of care enzalutamide and docetaxel.