Abstract 2174: Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas.

Abstract

Abstract The proto-oncogene PIM kinases (PIM-1, PIM-2, PIM-3) are serine/threonine kinases that have been shown to be involved in a number of signaling pathways important to cancer cells. PIM kinases act as downstream effectors as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, prostate, gastric, and head & neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma, and to assess for expression that may contribute to disease progression and serve as a potential site for targeted therapy. Seventy-two cases of urothelial carcinoma were included in this retrospective study of surgical biopsy and resection specimens from the University of Utah Department of Pathology (retrieved from 2008-2011). Tissue was stained with commercially available antibodies against PIM-1, PIM-2, and PIM-3. Cases were divided into three groups (invasive high grade urothelial carcinoma (n=49), non-invasive urothelial carcinoma/carcinoma in situ (n=16), and non-invasive low grade urothelial carcinoma (n=7)). Individual cases were then given a score (0-4) based upon a percentage of cells staining positive for each antibody (<5%=0; 5-25%=1; 26-50%=2; 51-75%=3; >75%=4). A score of 2 or greater was considered expressed. PIM-1, PIM-2 and PIM-3 expression was noted in 29% (2/7), 43% (3/7) and 86% (6/7) cases of non-invasive low-grade urothelial carcinoma; 44% (7/16), 50% (8/16), 44% (7/16) cases of non-invasive high-grade urothelial carcinoma; 10% (5/49), 27% (13/49), and 18% (9/49) cases of invasive high-grade urothelial carcinoma, respectively. These results suggest that expression of PIM-1, PIM-2 and PIM-3 is present in a significant percentage of urothelial carcinomas and may serve as a source for targeted PIM-kinase inhibition. We have developed PIM inhibitors exhibiting 4-10 fold improved potency against the PIM kinase family compared to our original PIM inhibitor SGI-1776. Our PIM inhibitors display sub-μM activity in pharmacodynamic marker modulation, proliferation and 2D colony formation assays using the UM-UC-3 bladder cancer cell line. These PIM kinase inhibitors also are potent inducers of apoptosis in T24, RT4, and UM-UC-3 bladder cancer cell lines. These compounds have favorable hERG and CYP inhibition profiles compared with SGI-1776, and demonstrate excellent oral bioavailability. In vivo xenograft studies using bladder cancer cell line models show that PIM kinase inhibition can reduce the tumor growth of these tumor models suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas. Citation Format: Kent J. Carpenter, Rachel Brog, Christopher Moreno, Daniel J. Albertson, Jared J. Bearss, Ting Liu, Steven Warner, David J. Bearss. Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas. [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 2174. doi:10.1158/1538-7445.AM2013-2174