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Grant

DYRK1B Inhibition for Prostate Cancer

Sponsored by National Center for Advancing Translational Sciences

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$153.5K Funding
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Abstract

Background: DYRK1B one of the kinases specified in this RFA is the key regulator of steady state turnover ofthe gatekeeper prostate cancer suppressor protein NKX3.1. NKX3.1 loss occurs in the majority of prostatecancers and the NKX3.1 is the most frequently deleted gene in prostate cancer. NKX3.1 is a haploinsufficientprotein and reduction of cellular protein levels by as little as 1/3 results in a neoplastic phenotype of prostateepithelial cells. However some NKX3.1 expression is retained even in advanced prostate cancer cells so thatthe residual protein expression is exploited by pathologists as a tissue specific marker for prostate cancer.Moreover NKX3.1 is a potent growth suppressor and differentiation factor. It follows that increasing NKX3.1levels is a logical therapeutic strategy to reverse the neoplastic phenotype of prostate cancer. To prove thevalidity of this approach we showed that whereas Nkx3.1+/- mice developed prostate hyperplasia and dysplasiawithin 6 months of age loss of the single Nkx3.1 Dyrk1b phosphorylation site at serine 186 essentially reversedthis phenotype in monoallelic Nkx3.1S186A/- mice. This remarkable finding provides preclinical justification toidentify DYRK1B inhibitors for the treatment of prostate cancer. We have also demonstrated that short-termadministration of a small molecule DYRK1B inhibitor to Nkx3.1+/- mice increased Nkx3.1 levels in prostateepithelial cells.Hypothesis: DYRK1B inhibition will increase intracellular Nkx3.1 resulting in retarded or reversed prostatecarcinogenesis epithelial cell differentiation and prostate cancer growth inhibition.Experiments: In a collaboration with Chris Hulme PhD Director of the University of Arizona BIO5 TranslationalDrug Discovery Center we will test a large panel of DYRK inhibitors from his lab. In the one year of this projectwe will identify the most potent and highest affinity inhibitors of DYRK1B by in vitro assay in LNCaP cells byassessing inhibition of NKX3.1 degradation. NKX3.1 half-life is ~30 minutes. Therefore screening drugcandidates can be done by treating cycloheximide-exposed cells for up to 3 hours and assaying for NKX3.1levels. In Aim 2 we will chose up to five of the agents most effective in vitro for administration over one week toNkx3.1+/- mice at different doses to determine the potency of each to increase Nkx3.1 expression levels in vivo.To assure drug availability in vivo we will conduct full KinomeScans and PK studies of each inhibitor to assurein vivo effectiveness. In addition we will conduct RNAseq analysis of Nkx3.1+/- prostate tissue after one week ofexposure to the most potent DYRK inhibitors to define their target pathways. As controls the inhibitors will beadministered over one week to Nkx3.1+/+ and Nkx3.1-/- mice to carry out RNAseq to identify on-target off-Nkx3.1gene expression effects and off-target effects. Comparison will also be made with prostate gene expression fromuntreated Nkx3.1S186A/- mice that have a missense mutation at the Dyrk1b phosphorylation site.

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