GHRH antagonists JMR-132 and JV-1-38 blocked the cross-talk between GHRH receptors and cancer-driving HER receptors in prostate cancer, inhibiting tumor growth in mice through reduced EGFR and HER2 expression.
Tumor growth inhibited with reduced EGFR/HER2GHRH antagonist JV-1-38 blocked peptide hormone-cancer receptor cross-talk and inhibited PC3 prostate cancer xenograft growth in mice
What the researchers found
In PC3 androgen-independent prostate cancer cells and nude mouse xenografts:
- GHRH stimulated expression and activation of both EGFR and HER2
- GHRH caused rapid ligand-independent HER activation via cAMP/PKA and Src pathways
- GHRH also caused slow ligand-dependent HER activation via ADAM-mediated extracellular pathway
- GHRH antagonists JMR-132 and JV-1-38 abrogated GHRH-stimulated responses in vitro
- EGF reciprocally increased GHRH and GHRH receptor mRNA — bidirectional cross-talk
- In vivo: JV-1-38 inhibited tumor growth with substantial reduction in EGFR/HER2 mRNA and protein
- JV-1-38 significantly decreased phosphorylated Src levels in tumors
Why it matters
Advanced prostate cancer that no longer responds to hormone therapy has limited treatment options. This study reveals a previously unknown connection between the peptide hormone GHRH and cancer-driving growth factor receptors, and shows that GHRH antagonist peptides can block this connection. This opens a new therapeutic strategy for one of the most aggressive forms of prostate cancer.
How the study worked
In vitro studies used PC3 human androgen-independent prostate cancer cells. GHRH effects on EGFR and HER2 expression and activation were assessed by time-course studies. GHRH antagonists JMR-132 and JV-1-38 were tested for receptor blocking. Signaling pathways were dissected using PKA and Src inhibitors. In vivo, nude mice bearing PC3 xenografts were treated with JV-1-38, and tumors were analyzed for EGFR, HER2, and Src expression.
What this study cannot tell us
The in vitro studies used a single cell line (PC3), which may not represent the diversity of prostate cancers. The in vivo xenograft model uses immunodeficient mice and may not fully reflect human tumor biology and immune interactions. The GHRH antagonists' effects on normal tissues and side effects were not assessed. The study focused on androgen-independent cancer; effects in earlier-stage prostate cancer are unknown.
How to read the evidence
This is a preclinical study with in vitro mechanistic data and in vivo mouse xenograft results. While it reveals important biology, no human prostate cancer patients have been treated with GHRH antagonists for this purpose.
When this study was published
Published in 2014, this study is part of the early exploration of GHRH antagonists as anti-cancer agents, an area that continues to be investigated.
The bigger picture
GHRH antagonists were originally developed to suppress growth hormone for conditions like acromegaly, but their anti-cancer properties have attracted growing interest. This study reveals a specific mechanism — blocking GHRH-HER cross-talk — that could be exploited in combination therapy. The finding of bidirectional communication between GHRH and EGF receptors adds complexity to our understanding of how peptide hormones influence cancer.
Questions still open
- Would combining GHRH antagonists with anti-EGFR or anti-HER2 drugs provide synergistic anti-tumor effects in prostate cancer?
- Do GHRH antagonists have anti-cancer effects in other tumor types that express EGFR/HER2?
- Could GHRH levels serve as a biomarker for predicting response to anti-HER therapies in prostate cancer?
Common questions
What are GHRH antagonists?
How does GHRH promote prostate cancer?
Read the original research
Growth hormone-releasing hormone antagonists abolish the transactivation of human epidermal growth factor receptors in advanced prostate cancer models.
Investigational new drugs, 32(5), 871-82
Citation
Muñoz-Moreno, Laura; Arenas, M Isabel; Carmena, M José; Schally, Andrew V; Prieto, Juan C; Bajo, Ana M. (2014). Growth hormone-releasing hormone antagonists abolish the transactivation of human epidermal growth factor receptors in advanced prostate cancer models.. Investigational new drugs, 32(5), 871-82. https://doi.org/10.1007/s10637-014-0131-4