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.
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.
|Keil, Kimberly P; Abler, Lisa L; Altmann, Helene M et al. (2016) Influence of animal husbandry practices on void spot assay outcomes in C57BL/6J male mice. Neurourol Urodyn 35:192-8|
|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|
|Gamat, Melissa; Malinowski, Rita L; Parkhurst, Linnea J et al. (2015) Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate. PLoS One 10:e0139522|
|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|
|Bauman, Tyler M; Vezina, Chad M; Huang, Wei et al. (2014) Beta-catenin is elevated in human benign prostatic hyperplasia specimens compared to histologically normal prostate tissue. Am J Clin Exp Urol 2:313-22|
|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|
|Keil, Kimberly P; Mehta, Vatsal; Branam, Amanda M et al. (2012) Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen-dependent prostate development. Endocrinology 153:6091-103|
|Nicholson, Tristan M; Ricke, Emily A; Marker, Paul C et al. (2012) Testosterone and 17?-estradiol induce glandular prostatic growth, bladder outlet obstruction, and voiding dysfunction in male mice. Endocrinology 153:5556-65|
|Buresh-Stiemke, Rita A; Malinowski, Rita L; Keil, Kimberly P et al. (2012) Distinct expression patterns of Sulf1 and Hs6st1 spatially regulate heparan sulfate sulfation during prostate development. Dev Dyn 241:2005-13|