There is a recognized clinical need to identify new molecular therapeutic targets for advanced prostate cancers that have failed androgen ablation therapy (i.e. castration-resistant prostate cancer). Furthermore, the frequent failure in the clinial setting of cancer drugs with demonstrable activity in xenograft models makes the testing of drug candidates in autochthonous animal models imperative. The overarching goal of this research program is to develop the oncogenic serine-threonine kinase PIM1 kinase as a therapeutic target in prostate cancer. PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia and by treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia and docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore PIM1 may represent a valuable therapeutic target in prostate cancer. To test this notion, we have developed new autochthonous mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We hypothesize that PIM1 promotes prostate tumorigenesis by phosphorylating key substrates involved in regulating MYC transcriptional acivity and stem cell function and that targeting PIM1 kinase activity is an effective strategy to treat MYC/PIM1- expressing prostate cancer. We will address these hypotheses via three aims. In the first aim, we will elucidate the mechanistic basis for cooperativity between MYC and PIM1 in prostate cancer. In the second aim, we will investigate the role of PIM1 in regulating stem cell renewal. In the third aim, we will test the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance in vivo. These studies should to provide us with novel insights into the mechanisms of PIM1 function in prostate cancer and rigorously test the effectiveness of new PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance.

Public Health Relevance

The studies outlined in this proposal will enhance our ability to treat prostate cancer, including castration-resistant prostate cancer as well as on reversing chemotherapeutic resistance. The novel animal models that will be used could in general provide us with valuable resources for testing new therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA123484-07
Application #
8640083
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
2006-07-01
Project End
2018-03-31
Budget Start
2014-04-29
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$276,202
Indirect Cost
$97,431
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Kirschner, Austin N; Wang, Jie; van der Meer, Riet et al. (2015) PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer. J Natl Cancer Inst 107:
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Holder, Sheldon L; Abdulkadir, Sarki A (2014) PIM1 kinase as a target in prostate cancer: roles in tumorigenesis, castration resistance, and docetaxel resistance. Curr Cancer Drug Targets 14:105-14
Anderson, Philip D; McKissic, Sydika A; Logan, Monica et al. (2012) Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis. J Clin Invest 122:1907-19
Kim, Seog-Young; Rhee, Juong G; Song, Xinxin et al. (2012) Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM. PLoS One 7:e50423

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