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Cancer Discovery
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Research Brief

Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention

Shidong Jia, Xueliang Gao, Sang Hyun Lee, Sauveur-Michel Maira, Xiaoqiu Wu, Edward C. Stack, Sabina Signoretti, Massimo Loda, Jean J. Zhao and Thomas M. Roberts
Shidong Jia
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Xueliang Gao
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Sang Hyun Lee
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Sauveur-Michel Maira
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Xiaoqiu Wu
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Edward C. Stack
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Sabina Signoretti
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Massimo Loda
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Jean J. Zhao
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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Thomas M. Roberts
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
Departments of 1Cancer Biology and 2Medical Oncology, Dana-Farber Cancer Institute; Departments of 3Biological Chemistry and Molecular Pharmacology and 4Pathology, Harvard Medical School, ­Boston, Massachusetts; and 5Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland
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DOI: 10.1158/2159-8290.CD-12-0262 Published January 2013
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Abstract

Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors have yielded encouraging yet ultimately confounding results. Using a preclinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, in which surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the phosphoinositide 3-kinase (PI3K) signaling pathway via either genetic ablation of genes encoding PI3K components or pharmacologic inhibition of the PI3K pathway reversed the PTEN loss–induced HG-PIN phenotype. Finally, concurrent inhibition of the PI3K and mitogen-activated protein kinase (MAPK) pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of antiandrogen chemoprevention in certain genetic contexts (such as PTEN loss) while showing the promise of targeted therapy in the clinical management of this complex and prevalent disease.

Significance: Chemoprevention with antiandrogen therapies is attractive for prostate cancer, given its prevalence and established hormonally mediated pathogenesis. However, because PTEN loss has been found in 9% to 45% of HG-PIN in the clinic, the current findings suggest that patients with PTEN-deficient prostate tumors might be better treated with PI3K-targeted therapies. Cancer Discov; 3(1); 44–51. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received June 7, 2012.
  • Revision received November 14, 2012.
  • Accepted November 15, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Discovery: 3 (1)
January 2013
Volume 3, Issue 1
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Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
Shidong Jia, Xueliang Gao, Sang Hyun Lee, Sauveur-Michel Maira, Xiaoqiu Wu, Edward C. Stack, Sabina Signoretti, Massimo Loda, Jean J. Zhao and Thomas M. Roberts
Cancer Discov January 1 2013 (3) (1) 44-51; DOI: 10.1158/2159-8290.CD-12-0262

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Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
Shidong Jia, Xueliang Gao, Sang Hyun Lee, Sauveur-Michel Maira, Xiaoqiu Wu, Edward C. Stack, Sabina Signoretti, Massimo Loda, Jean J. Zhao and Thomas M. Roberts
Cancer Discov January 1 2013 (3) (1) 44-51; DOI: 10.1158/2159-8290.CD-12-0262
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