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Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death

Carlos Perez-Stable1,2,3,4, Alicia de Las Pozas1, Medhi Wangpaichitr1,2,4,5,6

  • 1Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.

Cancers
|May 28, 2025
PubMed
Abstract

Insights

Combining GHRH antagonists with PI3K inhibitors significantly increases prostate cancer cell death. This combination targets key signaling pathways, offering a promising strategy for advanced prostate cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Growth hormone-releasing hormone (GHRH) antagonists show experimental therapeutic potential.
  • Single-agent GHRH antagonists are unlikely to improve outcomes in advanced prostate cancer, particularly castration-resistant forms.
  • Identifying synergistic drug combinations is crucial for enhancing treatment efficacy.

Purpose of the Study:

  • To identify anti-cancer drugs that synergize with GHRH antagonists (MIA-602/690) to induce cell death in all prostate cancer types.
  • To investigate the molecular mechanisms underlying the combination therapy's effects.

Main Methods:

  • Screening for drugs that enhance cell death when combined with MIA-602/690 GHRH antagonists.
  • Analyzing the impact of combination therapy on key signaling pathways, including PI3K/AKT/mTOR, apoptosis, and proliferation.
  • Utilizing both MIA-602/690 and its clinically relevant acetate salt form.

Main Results:

  • Inhibitors of PI3Kα or PI3Kβ consistently increased cell death in combination with MIA-602/690.
  • The combination therapy modulated multiple signaling pathways, including switching Mcl-1L to Mcl-1S, affecting E2F1 and cyclin A, and impacting PI3Kα/β, AKT, and ERK.
  • MIA-602/690 alone decreased androgen receptors and potentially enhanced PI3K via negative feedback, which was counteracted by PI3K inhibitors.

Conclusions:

  • The combination of MIA-602/690 and PI3K inhibitors demonstrates significant anti-cancer activity in prostate cancer models.
  • This combination therapy may overcome adaptive resistance mechanisms by targeting multiple critical signaling pathways.
  • The findings highlight PI3K as a significant drug target in prostate cancer, given the high frequency of PTEN loss and PIK3CA alterations.
Keywords:
AKTERKMcl-1PI3Kandrogen receptorgrowth hormone-releasing hormone antagonistprostate cancer

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