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GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and

Vito Cucchiara1, Joy C Yang1, Chengfei Liu1

  • 1Department of Urologic Surgery, University of California at Davis, Sacramento, California.

Molecular Cancer Therapeutics
|July 26, 2019
PubMed

Insights

Degarelix, a GnRH antagonist, effectively reduced prostate cancer cell viability and suppressed tumor growth by inhibiting androgen steroidogenesis. Unlike GnRH agonists like leuprolide, degarelix demonstrated a direct anti-cancer effect and reduced AR-V7 expression.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Hormone therapy is the standard treatment for advanced prostate cancer.
  • Gonadotropin-releasing hormone (GnRH) receptor antagonists, like degarelix, offer an alternative to GnRH agonists (e.g., leuprolide).
  • Degarelix avoids testosterone flare and lowers follicle-stimulating hormone (FSH) levels, distinguishing it from GnRH agonists.

Purpose of the Study:

  • To evaluate the direct effects of degarelix and leuprolide on prostate cancer cells.
  • To compare the efficacy of degarelix and leuprolide in inhibiting tumor growth and androgen production in vivo.
  • To investigate the impact of degarelix on androgen receptor variants (AR-V7).

Main Methods:

  • In vitro studies using LNCaP, C4-2BMDVR, and CWR22Rv1 prostate cancer cell lines.
  • In vivo studies using SCID mice xenograft models (VCaP tumors).
  • Treatment groups included surgical castration, degarelix, leuprolide, and buffer control.
  • Analysis of cell viability, AR-V7 protein expression, tumor growth, and intratumoral steroid levels via LC/MS.

Main Results:

  • Degarelix significantly reduced prostate cancer cell viability (P ≤ 0.01), while leuprolide was stimulatory.
  • Degarelix decreased AR-V7 protein expression in C4-2B MDVR cells, alone or with abiraterone/enzalutamide.
  • In vivo, degarelix suppressed tumor growth more effectively than leuprolide and comparable to surgical castration.
  • Degarelix significantly reduced testosterone and steroidogenesis intermediates, unlike leuprolide.

Conclusions:

  • Degarelix exhibits a direct anti-cancer mechanism by inhibiting androgen steroidogenesis and affecting AR-variants.
  • Degarelix demonstrates superior efficacy compared to GnRH agonists like leuprolide in preclinical models.
  • These findings provide molecular insights into degarelix's mechanism, suggesting potential clinical advantages over GnRH agonist therapy for prostate cancer.

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