Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer

Kimberly McClinch, Rita A. Avelar, David Callejas, Sudeh Izadmehr, Danica Wiredja, Abbey Perl, Jaya Sangodkar, David B. Kastrinsky, Daniela Schlatzer, Maxwell Cooper, Janna Kiselar, Agnes Stachnik, Shen Yao, Divya Hoon, Daniel McQuaid, Nilesh Zaware, Yixuan Gong, David L. Brautigan, Stephen R. Plymate, Cynthia C.T. SprengerWilliam K. Oh, Alice C. Levine, Alexander Kirschenbaum, John P. Sfakianos, Rosalie Sears, Analisa DiFeo, Yiannis Ioannou, Michael Ohlmeyer, Goutham Narla, Matthew D. Galsky

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2065-2080
Number of pages16
JournalCancer Research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

Fingerprint

Castration
Prostatic Neoplasms
Androgen Receptors
Proteins
Phosphoprotein Phosphatases
Neoplasms
Sulfonamides
Heterografts
Androgens
Protein Isoforms
Phosphotransferases
Down-Regulation
Apoptosis
Recurrence
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McClinch, K., Avelar, R. A., Callejas, D., Izadmehr, S., Wiredja, D., Perl, A., ... Galsky, M. D. (2018). Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer. Cancer Research, 78(8), 2065-2080. https://doi.org/10.1158/0008-5472.CAN-17-0123

Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer. / McClinch, Kimberly; Avelar, Rita A.; Callejas, David; Izadmehr, Sudeh; Wiredja, Danica; Perl, Abbey; Sangodkar, Jaya; Kastrinsky, David B.; Schlatzer, Daniela; Cooper, Maxwell; Kiselar, Janna; Stachnik, Agnes; Yao, Shen; Hoon, Divya; McQuaid, Daniel; Zaware, Nilesh; Gong, Yixuan; Brautigan, David L.; Plymate, Stephen R.; Sprenger, Cynthia C.T.; Oh, William K.; Levine, Alice C.; Kirschenbaum, Alexander; Sfakianos, John P.; Sears, Rosalie; DiFeo, Analisa; Ioannou, Yiannis; Ohlmeyer, Michael; Narla, Goutham; Galsky, Matthew D.

In: Cancer Research, Vol. 78, No. 8, 15.04.2018, p. 2065-2080.

Research output: Contribution to journalArticle

McClinch, K, Avelar, RA, Callejas, D, Izadmehr, S, Wiredja, D, Perl, A, Sangodkar, J, Kastrinsky, DB, Schlatzer, D, Cooper, M, Kiselar, J, Stachnik, A, Yao, S, Hoon, D, McQuaid, D, Zaware, N, Gong, Y, Brautigan, DL, Plymate, SR, Sprenger, CCT, Oh, WK, Levine, AC, Kirschenbaum, A, Sfakianos, JP, Sears, R, DiFeo, A, Ioannou, Y, Ohlmeyer, M, Narla, G & Galsky, MD 2018, 'Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer', Cancer Research, vol. 78, no. 8, pp. 2065-2080. https://doi.org/10.1158/0008-5472.CAN-17-0123
McClinch, Kimberly ; Avelar, Rita A. ; Callejas, David ; Izadmehr, Sudeh ; Wiredja, Danica ; Perl, Abbey ; Sangodkar, Jaya ; Kastrinsky, David B. ; Schlatzer, Daniela ; Cooper, Maxwell ; Kiselar, Janna ; Stachnik, Agnes ; Yao, Shen ; Hoon, Divya ; McQuaid, Daniel ; Zaware, Nilesh ; Gong, Yixuan ; Brautigan, David L. ; Plymate, Stephen R. ; Sprenger, Cynthia C.T. ; Oh, William K. ; Levine, Alice C. ; Kirschenbaum, Alexander ; Sfakianos, John P. ; Sears, Rosalie ; DiFeo, Analisa ; Ioannou, Yiannis ; Ohlmeyer, Michael ; Narla, Goutham ; Galsky, Matthew D. / Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer. In: Cancer Research. 2018 ; Vol. 78, No. 8. pp. 2065-2080.
@article{f694e81ca4ae4777a3c2c7c97b444d1e,
title = "Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer",
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.",
author = "Kimberly McClinch and Avelar, {Rita A.} and David Callejas and Sudeh Izadmehr and Danica Wiredja and Abbey Perl and Jaya Sangodkar and Kastrinsky, {David B.} and Daniela Schlatzer and Maxwell Cooper and Janna Kiselar and Agnes Stachnik and Shen Yao and Divya Hoon and Daniel McQuaid and Nilesh Zaware and Yixuan Gong and Brautigan, {David L.} and Plymate, {Stephen R.} and Sprenger, {Cynthia C.T.} and Oh, {William K.} and Levine, {Alice C.} and Alexander Kirschenbaum and Sfakianos, {John P.} and Rosalie Sears and Analisa DiFeo and Yiannis Ioannou and Michael Ohlmeyer and Goutham Narla and Galsky, {Matthew D.}",
year = "2018",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-17-0123",
language = "English (US)",
volume = "78",
pages = "2065--2080",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

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.

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

UR - http://www.scopus.com/inward/citedby.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

VL - 78

SP - 2065

EP - 2080

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -