title: 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.
authors.affiliation: The 6th People's Hospital, Shanghai Jiaotong University, Shanghai, 200233, China.|Icahn School of Medicine, Mount Sinai Medical Center, New York, NY, 10029, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Icahn School of Medicine, Mount Sinai Medical Center, New York, NY, 10029, USA.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Garcia
authors.affiliation: The Prostate Centre at Vancouver General Hospital Vancouver, British Columbia, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Prostate Centre at Vancouver General Hospital Vancouver, British Columbia, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Oncotide Pharmaceuticals, Research Triangle Park, NC, 27709, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.affiliation: Oncotide Pharmaceuticals, Research Triangle Park, NC, 27709, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Oncotide Pharmaceuticals, Research Triangle Park, NC, 27709, USA.|Division of Hematology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Christensen
authors.affiliation: Icahn School of Medicine, Mount Sinai Medical Center, New York, NY, 10029, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mulholland
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D051059:PTEN Phosphohydrolase; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C583613:OP449 peptide; C513473:SET protein, human; C494929:PTEN protein, human