2. Academic Validation
  3. Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer

Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer

  • Cancer Res. 2018 Apr 15;78(8):2065-2080. doi: 10.1158/0008-5472.CAN-17-0123.
Kimberly McClinch  # 1,  Rita A Avelar  # 2,  David Callejas  # 2,  Sudeh Izadmehr  # 1 3,  Danica Wiredja 4,  Abbey Perl 2,  Jaya Sangodkar 3,  David B Kastrinsky 5,  Daniela Schlatzer 4,  Maxwell Cooper 2,  Janna Kiselar 4,  Agnes Stachnik 3,  Shen Yao 6,  Divya Hoon 3,  Daniel McQuaid 3,  Nilesh Zaware 5,  Yixuan Gong 1,  David L Brautigan 7,  Stephen R Plymate 8,  Cynthia C T Sprenger 8,  William K Oh 1,  Alice C Levine 6,  Alexander Kirschenbaum 9,  John P Sfakianos 9,  Rosalie Sears 10,  Analisa DiFeo 11,  Yiannis Ioannou 3,  Michael Ohlmeyer 5,  Goutham Narla 12 11,  Matthew D Galsky 13
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 2 Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 5 Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio.
  • 6 Department of Medicine, Division of Endocrine, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 7 Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia.
  • 8 Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
  • 9 Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 10 Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
  • 11 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
  • 12 Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, Ohio. matthew.galsky@mssm.edu goutham.narla@case.edu.
  • 13 Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. matthew.galsky@mssm.edu goutham.narla@case.edu.
  • # Contributed equally.
PMID: 29358171 DOI: 10.1158/0008-5472.CAN-17-0123
Abstract

Primary prostate Cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate Cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the Androgen Receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein Phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced Apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine Phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the Androgen Receptor in advanced prostate Cancer. Cancer Res; 78(8); 2065-80. ©2018 AACR.

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