TY - JOUR
T1 - Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer
AU - McClinch, Kimberly
AU - Avelar, Rita A.
AU - Callejas, David
AU - Izadmehr, Sudeh
AU - Wiredja, Danica
AU - Perl, Abbey
AU - Sangodkar, Jaya
AU - Kastrinsky, David B.
AU - Schlatzer, Daniela
AU - Cooper, Maxwell
AU - Kiselar, Janna
AU - Stachnik, Agnes
AU - Yao, Shen
AU - Hoon, Divya
AU - McQuaid, Daniel
AU - Zaware, Nilesh
AU - Gong, Yixuan
AU - Brautigan, David L.
AU - Plymate, Stephen R.
AU - Sprenger, Cynthia C.T.
AU - Oh, William K.
AU - Levine, Alice C.
AU - Kirschenbaum, Alexander
AU - Sfakianos, John P.
AU - Sears, Rosalie
AU - DiFeo, Analisa
AU - Ioannou, Yiannis
AU - Ohlmeyer, Michael
AU - Narla, Goutham
AU - Galsky, Matthew D.
N1 - Funding Information:
D.B. Kastrinsky has ownership interest (including patents) in Dual Therapeutics. D.L. Brautigan reports receiving a commercial research grant from Bristol–Myers Squibb and is a consultant/advisory board member for Dual Therapeutics and Bristol-Myers Squibb. M. Ohlmeyer is a consultant at Dual Therapeutics LLC, reports receiving a commercial research grant from Dual Therapeutics LLC, has ownership interest (including patents) in Dual Therapeutics, and is a consultant/advisory board member for Dual Therapeutics LLC. M.D. Galsky has ownership interest (including patents) in Dual Therapeutics. The Icahn School of Medicine at Mount Sinai, on behalf of G. Narla and M. Ohlmeyer, has filed patents covering composition of matter on the small molecules disclosed herein for the treatment of human cancer and other diseases (International Application Numbers: PCT/US15/19770, PCT/US15/ 19764; and US Patent: US 9,540,358 B2). RAPPTA Therapeutics LLC has licensed this intellectual property for the clinical and commercial development of this series of small-molecule PP2A activators. G. Narla, M. Ohlmeyer, and M.D. Galsky have an ownership interest in RAPPTA Therapeutics LLC. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We gratefully acknowledge the New York City Investment Fund (Bio-accelerate Prize) and Dual Therapeutics/BioMotiv for continued support. G. Narla received a Howard Hughes Medical Institute (HHMI) Physician-Scientist Early Career Award and a Case Comprehensive Cancer Center Pilot Award. S. Izadmehr is a LRP awardee (NCATS/NIH). This work was partially supported by an NCI/NIH R01 grant 1R01CA181654-01A1 (G. Narla, M.D. Galsky, M. Ohlmeyer, and A.C. Levine), DoD grant W81XWH-15-1-0596 (M.D. Galsky), and Prostate Cancer Foundation Young Investigator Award (M.D. Galsky).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047873789&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0123
DO - 10.1158/0008-5472.CAN-17-0123
M3 - Article
C2 - 29358171
AN - SCOPUS:85047873789
SN - 0008-5472
VL - 78
SP - 2065
EP - 2080
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -