Abstract 2080: Inhibiting androgen receptor-associated Src signaling by VAL201 inhibits prostate cancer metastasis in an orthotopic mouse model.
Authors: Morris George S. , Suominen Mari I. , Fagerlund Katja M. , Rissanen Jukka-Pekka , Halleen Jussi M. , Vainikka Satu 
Published: August 2014

Abstract
VAL201 is a specific inhibitor of androgen receptor (AR) and estrogen receptor (ER) associated src signaling that has shown promising effects to reduce prostate cancer growth, and the compound is considered as a potential treatment for castration-resistant prostate cancer. Inhibition of src by VAL201 takes place after androgen binding, allowing inhibition of growth without blocking desirable receptor-dependent transcriptional activity, and thereby eliminating the majority of side effects associated with androgen deprivation therapies. The ER positive human prostate cancer cell line PC-3 is usually cited as AR negative, but there is evidence of low levels of AR expression as a form without transcriptional activity that could associate with src. We have studied the effects of Val201 on PC-3 cell proliferation in vitro and growth and metastasis in vivo in an orthotopic xenograft model. The proliferation effects were studied for 100 pM, 1 nM, 10 nM, 100 nM and 1 μM concentrations of VAL201 by measuring WST-1 values at days 3, 5, 7 and 9. Groups with vehicle and 1 μM gemcitabine as reference compound were included in the study. The xenograft study was performed with 6-7 week-old immunodeficient BALB/c nude mice that were allocated to 6 groups (with n=15/group) according to the body weight, one group receiving vehicle and the others VAL201 at doses 0.04, 0.4, 4, 10 and 20 mg/kg. PC-3 cells in Matrigel were inoculated orthotopically into the prostate. Subcutaneous dosing was started at day 1 and continued daily for 28 days. The mice were weighed twice a week. Orthotopic tumors were measured by caliper and the prostate and the regional lymph nodes were harvested at sacrifice. Metastases in lymph nodes were determined from HE stained paraffin sections. VAL201 showed dose-dependent inhibition of PC-3 cell proliferation that was statistically significant with all doses above 100 pM. In the xenograft study VAL201 had no effect on body weight. Statistically significant effects on orthotopic tumor growth were not observed despite of a 35% decrease observed in tumor volume with the 0.4 mg/kg dose. However, 0.04 and 0.4 mg/kg doses of VAL201 showed a significant 50% inhibition of the development of lymph node metastases. As a conclusion, VAL201 inhibited proliferation of PC-3 cells in vitro and development of lymph node metastases in a xenograft model, demonstrating its potential in inhibiting prostate cancer growth and metastasis without adverse effects associated with androgen deprivation.
Citation Format: George S. Morris, Mari I. Suominen, Katja M. Fagerlund, Jukka-Pekka Rissanen, Jussi M. Halleen, Satu Vainikka. Inhibiting androgen receptor-associated Src signaling by VAL201 inhibits prostate cancer metastasis in an orthotopic mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2080. doi:10.1158/1538-7445.AM2013-2080