The proto-oncogene proviral integration site for moloney murine leukemia virus (
PIM) kinases (PIM-1, PIM-2, and PIM-3) are
serine/threonine kinases that are involved in a number of signaling pathways important to
cancer cells.
PIM kinases act in downstream effector functions 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, and prostate, gastric, and head and
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 the role PIM function in
disease progression and their potential to serve as molecular targets for
therapy. One hundred thirty-seven cases of urothelial
carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial
carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic
biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3
bladder cancer cell line. TP-3654 displays favorable human
ether-à-go-go-related gene and
cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor,
SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a
bladder cancer cell line show that PIM
kinase inhibition can reduce
tumor growth, suggesting that PIM
kinase inhibitors may be active in human urothelial
carcinomas.