Antagonists of LHRH and GHRH receptors, plus the targeted cytotoxic LHRH analog AN-152, show preclinical promise for treating triple-negative breast cancer — a subtype with few treatment options.
TNBC expresses LHRH and GHRH receptorsA substantial proportion of triple-negative breast cancers — which lack all three standard drug targets — express receptors for peptide hormones LHRH and GHRH, opening new therapeutic possibilities.
What the researchers found
A substantial proportion of triple-negative breast cancers express receptors for both LHRH and GHRH, providing potential therapeutic targets. Potent antagonists of both GHRH and LHRH receptors have been developed and shown to inhibit tumor growth, tumorigenicity, and metastatic potential in experimental cancer models.
The targeted cytotoxic LHRH analog AN-152 (AEZS-108), which conjugates the chemotherapy drug doxorubicin to an LHRH peptide, delivers chemotherapy directly to LHRH receptor-expressing cancer cells. This approach could provide targeted treatment for TNBC while reducing systemic toxicity. The authors conclude that experimental evidence supports clinical trials with LHRH antagonists and AN-152 in TNBC patients.
Why it matters
TNBC accounts for about 15-20% of breast cancers and has the worst prognosis because it lacks the molecular targets (ER, PR, HER2) used by most breast cancer drugs. Chemotherapy is the only systemic option but responses are disappointing. Peptide hormone receptor-based therapies could provide the first targeted treatments for this aggressive cancer, potentially improving outcomes while reducing the side effects of untargeted chemotherapy.
How the study worked
Review of experimental and preclinical studies examining the expression of LHRH and GHRH receptors in TNBC, and the antitumor effects of LHRH antagonists, GHRH antagonists, and the targeted cytotoxic LHRH analog AN-152 (AEZS-108) in cancer models.
What this study cannot tell us
This is a review of preclinical and experimental data — no clinical trial results are presented. The proportion of TNBC tumors that express sufficient LHRH/GHRH receptors for therapy is not precisely quantified. Clinical translation of peptide-based cancer therapies faces challenges including receptor heterogeneity, peptide stability, and achieving adequate tumor penetration. The publication is from 2012, and subsequent clinical trials may have provided additional data.
How to read the evidence
This is a review of preclinical and experimental data. While the rationale is strong and the receptor expression data are compelling, no clinical trial results in TNBC patients were available at the time of publication.
When this study was published
Published in 2012, this review was ahead of its time in proposing peptide-targeted therapies for TNBC. Since then, TNBC treatment has evolved with immunotherapy and ADCs, but peptide receptor targeting remains a relevant approach.
The bigger picture
Peptide hormone analogs have a long history in oncology — LHRH agonists are standard treatment for prostate cancer and some breast cancers. Extending this approach to TNBC through receptor-targeted antagonists and cytotoxic conjugates represents an innovative application of peptide pharmacology. The concept of using peptide hormones to deliver chemotherapy directly to tumors (like AN-152) is an early precursor to modern antibody-drug conjugate strategies.
Questions still open
- Have clinical trials of AN-152 or LHRH/GHRH antagonists in TNBC patients yielded positive results since this review?
- What proportion of TNBC tumors express enough LHRH/GHRH receptors to benefit from these targeted therapies?
- Could combination approaches using both LHRH and GHRH antagonists provide synergistic antitumor effects?
Common questions
Why is triple-negative breast cancer so hard to treat?
How could a peptide deliver chemotherapy to cancer cells?
Read the original research
Search for novel therapies for triple negative breast cancers (TNBC): analogs of luteinizing hormone-releasing hormone (LHRH) and growth hormone-releasing hormone (GHRH).
Hormone molecular biology and clinical investigation, 9(1), 87-94
Citation
Buchholz, Stefan; Seitz, Stephan; Engel, Jörg B; Montero, Alberto; Ortmann, Olaf; Perez, Roberto; Block, Norman L; Schally, Andrew V. (2012). Search for novel therapies for triple negative breast cancers (TNBC): analogs of luteinizing hormone-releasing hormone (LHRH) and growth hormone-releasing hormone (GHRH).. Hormone molecular biology and clinical investigation, 9(1), 87-94. https://doi.org/10.1515/hmbci-2011-0002