Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer

Christopher C. Coss, Amanda Jones, Deanna N. Parke, Ramesh Narayanan, Christina M. Barrett, Jeffrey D. Kearbey, Karen A. Veverka, Duane Miller, Ronald A. Morton, Mitchell S. Steiner, James T. Dalton

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

Original languageEnglish (US)
Pages (from-to)1070-1081
Number of pages12
JournalEndocrinology
Volume153
Issue number3
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Prostatic Neoplasms
Hormones
Estrogens
Androgens
Hot Flashes
Therapeutics
Gonadotropin-Releasing Hormone
Non-Steroidal Estrogens
diphenyl
benzamide
Thrombophilia
Castration
Prostate-Specific Antigen
Osteoporosis
Disease-Free Survival
Weight Gain
Testosterone
Prostate
Survival Rate
Animal Models

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer. / Coss, Christopher C.; Jones, Amanda; Parke, Deanna N.; Narayanan, Ramesh; Barrett, Christina M.; Kearbey, Jeffrey D.; Veverka, Karen A.; Miller, Duane; Morton, Ronald A.; Steiner, Mitchell S.; Dalton, James T.

In: Endocrinology, Vol. 153, No. 3, 01.03.2012, p. 1070-1081.

Research output: Contribution to journalArticle

Coss, CC, Jones, A, Parke, DN, Narayanan, R, Barrett, CM, Kearbey, JD, Veverka, KA, Miller, D, Morton, RA, Steiner, MS & Dalton, JT 2012, 'Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer', Endocrinology, vol. 153, no. 3, pp. 1070-1081. https://doi.org/10.1210/en.2011-1608
Coss, Christopher C. ; Jones, Amanda ; Parke, Deanna N. ; Narayanan, Ramesh ; Barrett, Christina M. ; Kearbey, Jeffrey D. ; Veverka, Karen A. ; Miller, Duane ; Morton, Ronald A. ; Steiner, Mitchell S. ; Dalton, James T. / Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer. In: Endocrinology. 2012 ; Vol. 153, No. 3. pp. 1070-1081.
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