Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.

Abstract

The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.

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Published Version (Please cite this version)

10.1038/srep15182

Publication Info

Hu, Xiaoyong, Consuelo Garcia, Ladan Fazli, Martin Gleave, Michael P Vitek, Marilyn Jansen, Dale Christensen, David J Mulholland, et al. (2015). Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis. Sci Rep, 5. p. 15182. 10.1038/srep15182 Retrieved from https://hdl.handle.net/10161/16047.

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Scholars@Duke

Vitek

Michael P. Vitek

Adjunct Associate Professor in Neurology

The overall interest of my laboratory is to identify the underlying causes of neurodegenerative diseases such as Alzheimer's disease. Once causes or experimental endpoints are determined, then strategies to find chemicals which can ameliorate pathophysiological events can be devised. In general, we are working to create transgenic animals and validate them as models of human disease.

Our specific approach has been to study the function of apolipoprotein-E (apoE) which Roses and colleagues found to a susceptibility factor for the presence of AD. Currently, our data are pointing to a relationship between apoE and oxidative stress where apoE appears to modulate nitric oxide production in a species specific manner. To further test this idea, we have created transgenic mice expressing the entire human NOS2 gene which will now be tested in various models of neurodegeneration and inflammation. Similarly, we are developing transgenic animals which express the human TAU gene. When properly stressed, these TAU-transgenic animals may display the neurofibrillary tangle pathology which is associated with neurodegeneration in a wide variety of neurological diseases.

If our transgenic animals prove to be validated models of human
disease, then the process to screen for chemicals which might alter the disease outcome in those models can begin in earnest. Should compounds be identified, then the various phases of clinical trials may proceed.

At present, my community service includes participation on the Alzheimer's Association Medical and Scientific Advisory Board and on the Neurological Sciences III Study Section for the National Institutes of Health extramural research program. I have previously served in a similar capacity for the American Health Assistance Foundation and the Long Island Alzheimer's Foundation. I have also had the pleasure to serve as a scientific consultant for various biotechnology companies.

Keywords: Neurodegeneration, Alzheimer's, Transgenic, Animal Models, Amyloid, Apolipoprotein-E, Molecular Biology, Biochemistry


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