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 #
2R01CA123484-06A1
Application #
8521709
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
2006-07-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$280,943
Indirect Cost
$96,643
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
van der Meer, Riet; Song, Ha Yong; Park, Seong-Hoon et al. (2014) RNAi screen identifies a synthetic lethal interaction between PIM1 overexpression and PLK1 inhibition. Clin Cancer Res 20:3211-21
Desouki, Mohamed Mokhtar; Doubinskaia, Irina; Gius, David et al. (2014) Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Hum Pathol 45:1071-7
Roh, Meejeon; van der Meer, Riet; Abdulkadir, Sarki A (2012) Tumorigenic polyploid cells contain elevated ROS and ARE selectively targeted by antioxidant treatment. J Cell Physiol 227:801-12
Wang, J; Anderson, P D; Luo, W et al. (2012) Pim1 kinase is required to maintain tumorigenicity in MYC-expressing prostate cancer cells. Oncogene 31:1794-803
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, J; Roh, M; Doubinskaia, I et al. (2012) A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene 31:322-32
Kim, Hyun-Seok; Patel, Krish; Muldoon-Jacobs, Kristi et al. (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17:41-52
Kim, Jongchan; Roh, Meejeon; Abdulkadir, Sarki A (2010) Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity. BMC Cancer 10:248
Wang, J; Kim, J; Roh, M et al. (2010) Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma. Oncogene 29:2477-87
Roh, Meejeon; Abdulkadir, Sarki A (2010) Targeting the endothelin receptor in prostate cancer bone metastasis: Back to the mouse? Cancer Biol Ther 9:615-7

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