Abstract 922: Inhibiting androgen receptor associated Src signaling with VAL201 inhibits breast cancer growth in an orthotopic xenograft model.
Authors: Suominen Mari I. , Morris George S. , Fagerlund Katja M. , Rissanen Jukka-Pekka , Vainikka Satu , Halleen Jussi M. 
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 in cancer cell cultures and animal models. 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. Majority of breast cancers are ER positive, and the hormonal treatment includes depletion of estrogen by antiestrogens or aromatase inhibitors (AIs). However, 88% of ER positive and 20-30% of ER negative breast cancers are AR positive, and recently some have been shown to be dependent on AR signaling. Furthermore, AI therapy can increase the androgen levels, as androgens are no longer converted to estrogens. We have studied the effects of Val201 on breast cancer growth in a xenograft model using estrogen-dependent, AR expressing MCF-7 breast cancer cells. Five-week old athymic nude mice were allocated to groups according to body weight (n=10/group). Slow releasing pellets containing 0.72 mg of 17β-estradiol for 60 day release were implanted one day before the cell inoculation. MCF-7 human mammary adenocarcinoma cells were cultured in standard cell culture conditions until semiconfluent and inoculated into the inguinal mammary fat pad at day 0. Vehicle and VAL201 at doses 0.004, 0.04, 0.4 and 4.0 mg/kg were administered sc daily for 28 days starting at day 1. Tumor growth was monitored by caliper measurements three times a week, and the tumors were weighed at sacrifice. VAL201 had no effect on body weight. Tumor volume growth curves demonstrated a dose-dependent inhibition of tumor growth by VAL201. Similar responses enabled combining the treatment groups to a low-dose group (including the groups receiving 0.004 and 0.04 mg/kg VAL201) and a high-dose group (including the groups receiving 0.4 and 4.0 mg/kg VAL201) to increase statistical power in further analyses. The combined groups demonstrated that VAL201 decreased tumor volume and weight. As a conclusion, VAL201 showed inhibition of breast cancer growth in this orthotopic xenograft model, demonstrating its potential as a novel therapeutic agent for breast cancer. The growth inhibition was established in the presence of estrogen, underlining the importance of androgen receptor-associated src signaling even without estrogen depletion.
Citation Format: Mari I. Suominen, George S. Morris, Katja M. Fagerlund, Jukka-Pekka Rissanen, Satu Vainikka, Jussi M. Halleen. Inhibiting androgen receptor associated Src signaling with VAL201 inhibits breast cancer growth in an orthotopic xenograft 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 922. doi:10.1158/1538-7445.AM2013-922