A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas

Jason M. Foulks, Kent J. Carpenter, Bai Luo, Yong Xu, Anna Senina, Rebecca Nix, Ashley Chan, Adrianne Clifford, Marcus Wilkes, David Vollmer, Benjamin Brenning, Shannon Merx, Shuping Lai, Michael V. McCullar, Koc Kan Ho, Daniel J. Albertson, Lee T. Call, Jared J. Bearss, Sheryl Tripp, Ting LiuBret J. Stephens, Alexis Mollard, Steven L. Warner, David J. Bearss, Steven B. Kanner

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)403-412
Number of pages10
JournalNeoplasia
Volume16
Issue number5
DOIs
StatePublished - Jan 1 2014

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Phosphotransferases
Carcinoma
Urinary Bladder Neoplasms
Neoplasms
Moloney murine leukemia virus
Therapeutics
Cell Line
Proto-Oncogenes
Protein-Serine-Threonine Kinases
G1 Phase
Head and Neck Neoplasms
Multiple Myeloma
S Phase
Heterografts
Ether
Cytochrome P-450 Enzyme System
Biological Availability
Stomach Neoplasms
Disease Progression
Prostate

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Medicine(all)

Cite this

Foulks, J. M., Carpenter, K. J., Luo, B., Xu, Y., Senina, A., Nix, R., ... Kanner, S. B. (2014). A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas. Neoplasia, 16(5), 403-412. https://doi.org/10.1016/j.neo.2014.05.004
Foulks, Jason M. ; Carpenter, Kent J. ; Luo, Bai ; Xu, Yong ; Senina, Anna ; Nix, Rebecca ; Chan, Ashley ; Clifford, Adrianne ; Wilkes, Marcus ; Vollmer, David ; Brenning, Benjamin ; Merx, Shannon ; Lai, Shuping ; McCullar, Michael V. ; Ho, Koc Kan ; Albertson, Daniel J. ; Call, Lee T. ; Bearss, Jared J. ; Tripp, Sheryl ; Liu, Ting ; Stephens, Bret J. ; Mollard, Alexis ; Warner, Steven L. ; Bearss, David J. ; Kanner, Steven B. / A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas. In: Neoplasia. 2014 ; Vol. 16, No. 5. pp. 403-412.
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abstract = "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-{\`a}-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.",
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Foulks, JM, Carpenter, KJ, Luo, B, Xu, Y, Senina, A, Nix, R, Chan, A, Clifford, A, Wilkes, M, Vollmer, D, Brenning, B, Merx, S, Lai, S, McCullar, MV, Ho, KK, Albertson, DJ, Call, LT, Bearss, JJ, Tripp, S, Liu, T, Stephens, BJ, Mollard, A, Warner, SL, Bearss, DJ & Kanner, SB 2014, 'A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas', Neoplasia, vol. 16, no. 5, pp. 403-412. https://doi.org/10.1016/j.neo.2014.05.004

A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas. / Foulks, Jason M.; Carpenter, Kent J.; Luo, Bai; Xu, Yong; Senina, Anna; Nix, Rebecca; Chan, Ashley; Clifford, Adrianne; Wilkes, Marcus; Vollmer, David; Brenning, Benjamin; Merx, Shannon; Lai, Shuping; McCullar, Michael V.; Ho, Koc Kan; Albertson, Daniel J.; Call, Lee T.; Bearss, Jared J.; Tripp, Sheryl; Liu, Ting; Stephens, Bret J.; Mollard, Alexis; Warner, Steven L.; Bearss, David J.; Kanner, Steven B.

In: Neoplasia, Vol. 16, No. 5, 01.01.2014, p. 403-412.

Research output: Contribution to journalArticle

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T1 - A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas

AU - Foulks, Jason M.

AU - Carpenter, Kent J.

AU - Luo, Bai

AU - Xu, Yong

AU - Senina, Anna

AU - Nix, Rebecca

AU - Chan, Ashley

AU - Clifford, Adrianne

AU - Wilkes, Marcus

AU - Vollmer, David

AU - Brenning, Benjamin

AU - Merx, Shannon

AU - Lai, Shuping

AU - McCullar, Michael V.

AU - Ho, Koc Kan

AU - Albertson, Daniel J.

AU - Call, Lee T.

AU - Bearss, Jared J.

AU - Tripp, Sheryl

AU - Liu, Ting

AU - Stephens, Bret J.

AU - Mollard, Alexis

AU - Warner, Steven L.

AU - Bearss, David J.

AU - Kanner, Steven B.

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N2 - 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.

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