Abstract 2534: Suppression of prostate cancer growth by the Src signaling inhibitor, KXO1 (KX2-391)

Abstract

Abstract KXO1 (KX2-391), developed as a Src tyrosine kinase signaling inhibitor, exhibits anti-proliferative activity against broad range of human cancer types in vitro, and has shown low toxicity in completed Phase I trials. We tested whether human and mouse prostate cancer (CaP) cell lines, which display activated levels of Src-family tyrosine kinases such as Src, Fyn and Lyn, could be inhibited by KXO1 compared to the broad tyrosine kinase inhibitor, Dasatinib (BMS-354825). Low nanomolar concentrations (9-75 nM) of KXO1 potently inhibited the proliferation of human CaP cell lines LNCaP, LNCaP-C4-2, PC3-LN4, LAPC-4 and DU145, and the CaP cell line, C2H, isolated from a castration-recurrent lesion in TRAMP mice. In contrast, whereas the GI50 of Dasatinib was equal to KXO1 for PC3-LN4 cells (9 nM), the GI50 for Dasatinib in LNCaP and DU145 cells was 10- and 2.7-fold higher than for KXO1, and Dasatinib failed to inhibit the proliferation of LNCaP-C4-2 cells at 10 μM. KXO1 exhibited a dose-dependent ability to inhibit anchorage-independent growth (AIG) of PC3-LN4, LNCaP and LNCaP-C4-2 cells. In contrast, Dasatinib caused less than 15% inhibition of AIG (compared to vehicle controls) in these CaP lines. Cell death, as measured by DNA fragmentation (Promega Cell Death ELISA kit), was induced after 24 h of KXO1 treatment (2-10X the GI50) of LNCaP and PC3-LN4 cells, but not induced by Dasatinib at 10X GI50 levels. We then tested the efficacy of KXO1 (vs. vehicle) in immunocompetent mice (C57BL/6) bearing small (∼150 mm3) syngeneic TRAMP C2H tumors using several treatment regimens that delivered 10 mg/kg/mouse/day. Mice receiving constant oral dosing (drinking water containing KXO1 in 5% sucrose) showed a 35-40% decrease in tumor growth rate, whereas mice dosed by oral gavage once or twice daily showed initial tumor growths followed by regression. Data will be shown comparing the efficacy of KXO1 against C2H tumors in immunocompetent versus SCID mice. Thus, KXO1 shows anti-CaP activity n vitro and in vivo irrespective of p53, AR or androgen-responsive status. Taken together, these data demonstrate strong preclinical evidence for the treatment of androgen-responsive and castration-recurrent CaP with KXO1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2534.