REGULATION OF PROSTATE CANCER CELL VIABILITY BY SMALL MOLECULE JAK2 INHIBITOR AZD1480 AND PROLACTIN RECEPTOR ANTAGONIST LFA102 VIA INHIBITION OF NUCLEAR STAT5 LEVELS IN in vivo PROSTATE XENOGRAFT TUMORS AND CLINICAL PROSTATE CANCERS ex vivo IN EXPLANT ORGAN CULTURES

S Blackmon1, MT Nevalainen1

1 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA.

There are currently no effective treatments for metastatic or castrate-resistant prostate cancer (PC). It has been shown that Stat5 is critical for PC cell viability in vitro and in vivo. Additionally, active Stat5a/b may serve as a prognostic/predictive marker for identification of primary PCs that are likely to progress to aggressive disease. Targeting critical steps in the canonical Prl-Jak2-Stat5a/b pathway may provide potential therapeutic approaches for treating castrate-resistant PC. We hypothesize that targeting Stat5 signaling with the Jak2 inhibitor AZD1480 and the prolactin receptor inhibitor LFA102 will lead to a decrease in PC cell viability and nuclear expression of Stat5a/b in xenograft PC tumor models in vivo and in clinical PCs tested ex vivo as organ explant cultures. We evaluated viability of PC tissue by H&E staining and nuclear Stat5 levels by immunohistochemistry in paraffin-embedded tissue samples. Additionally, we used In Situ End Labeling (ISEL) of fragmented DNA to evaluate the levels of apoptotic cells in the same samples. Epithelial cell viability was significantly decreased in xenograft tumors and clinical PC explants following treatment with AZD1480 (p< 0.001) and LFA102 (p<0.05), which also correlated with an increased level of apoptotic cells. Moreover, nuclear levels of Stat5a/b expression were significantly reduced following treatment with AZD1480 (p<0.005) and LFA102 (p<0.05) in both experimental model systems. Utilizing these two pharmacological inhibitors to target Stat5 may provide novel treatment strategies for castrate-resistant PC.