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Ref Type Journal Article
PMID (26563471)
Authors Hu X, Garcia C, Fazli L, Gleave M, Vitek MP, Jansen M, Christensen D, Mulholland DJ
Title Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.
Journal Vol Issue Date Pages Journal Short Title
Scientific reports 5 2015 Nov 13 15182 Sci Rep
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
OP449 OP449 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
OP449 PP2A Activator 7 OP449 is an activator of PP2A via inhibition of SET, which may reduce tumor size and block cell proliferation (PMID: 26563471, PMID: 32569675).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss prostate cancer sensitive OP449 Preclinical Actionable In a preclinical study, prostate cancer mouse models deficient for Pten demonstrated inhibition of the PI3K/Akt signaling pathway and a decrease in both tumor size and cell proliferation when treated with OP449 (PMID: 26563471). 26563471