Abstract
Abstract Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. Several small molecule PDE4D-selective inhibitors have been developed, including cilomilast and NVP-ABE171, and we have used them as potential anti-prostate cancer drugs in vitro and in vivo. The inhibitors were able to reduce the growth of prostate cancer cells in the context of epithelial mono-cultures or co-cultures that modeled stromal-epithelial interactions. Daily oral administration of PDE4D inhibitors for 6 weeks also reduced the growth of several prostate cancer xenograft lines in vivo through a dramatic induction of apoptosis. Interestingly, NVP-ABE171 and cilomilast also reduced the size of the prostates of treated mice without impacting overall animal health or the sizes of other organs. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition including the sonic hedgehog and mitogen-activated protein kinase pathways. We are continuing studies with these inhibitors to further support the use of NVP-ABE171 and cilomilast as anti-prostate cancer drugs and to understand their mechanism(s) of action in the prostate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1835. doi:1538-7445.AM2012-1835
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