We have conducted a two-species pilot screen to discover new oncogenes and tumor suppressor genes that can drive prostate cancer initiation and/or progression in mice and humans. The primary screen utilized transposon-based insertional mutagenesis in mice to model genetic heterogeneity in prostate cancer and conduct a genome-wide screen for new oncogenes and tumor suppressor genes. The secondary screen used human prostate cancer patient samples to validate the relevance of novel candidate cancer genes by examining the human orthologs of the genes for altered expression in human prostate cancers. This screen identified several novel candidate prostate cancer oncogenes and tumor suppressor genes. One of the first genes identified in the mouse screen, PDE4D, was also over-expressed in human prostate cancer patient samples. Furthermore, knockdown of PDE4D reduced the proliferation of human prostate cancer cells in vitro and in vivo. This proposal will investigate the novel candidate prostate cancer oncogenes and tumor suppressor genes that have been identified in our screen with a particular emphasis on evaluating the roles of PDE4D as a candidate prostate cancer oncogene and potential drug target in prostate cancer. Experiments in Aims 1 and 2 of the proposal will model PDE4D over-expression in the normal prostate and investigate the mechanism of PDE4D action in the prostate. Experiments in Aim 3 will test NVP- ABE171, a PDE4D-selective small molecule inhibitor, as a potential anti-prostate cancer drug in the context of pre-clinical models. Experiments in Aim 4 will evaluate the expression of PDE4D and other novel candidate prostate cancer genes identified in our preliminary studies for expression changes associated with different pathologic grades of human prostate cancer and/or expression that is predictive of long-term patient outcomes. Collectively, these studies will lead to a better understanding of the genetically diverse pathways that drive prostate cancer progression, and they will determine the suitability of PDE4D as a new drug target in prostate cancer.

Public Health Relevance

Statement Currently, there is insufficient understanding of the phenotypic and genetic heterogeneity among human prostate cancers to tailor prostate cancer treatment to the needs of individual patients. This project will lead to a better understanding of the genetically diverse pathways that drive prostate cancer progression in different prostate tumors. This will constitute an important step toward developing new diagnostic tests that can predict the best treatment option for individual prostate cancer patients. This project will also evaluate NVP-ABE171 as one potential new treatment for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140217-03
Application #
8204600
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Woodhouse, Elizabeth
Project Start
2010-03-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$294,345
Indirect Cost
$93,070
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Powers, Ginny L; Hammer, Kimberly D P; Domenech, Maribella et al. (2015) Phosphodiesterase 4D inhibitors limit prostate cancer growth potential. Mol Cancer Res 13:149-60
Hammer, Kimberly D P; Alsop, James D; Buresh-Stiemke, Rita A et al. (2014) A novel method for somatic transgenesis of the mouse prostate using the Sleeping Beauty transposon system. Prostate 74:781-91
Powers, Ginny L; Marker, Paul C (2013) Recent advances in prostate development and links to prostatic diseases. Wiley Interdiscip Rev Syst Biol Med 5:243-56