Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

• Published in: BMC cancer Vol. 14; no. 1; p. 847
• Main Authors: Seitz, Stephan, Buchholz, Stefan, Schally, Andrew Victor, Weber, Florian, Klinkhammer-Schalke, Monika, Inwald, Elisabeth C, Perez, Roberto, Rick, Ferenc G, Szalontay, Luca, Hohla, Florian, Segerer, Sabine, Kwok, Chui Wai, Ortmann, Olaf, Engel, Jörg Bernhard
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19-11-2014; BioMed Central
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; Female; Gonadotropin-Releasing Hormone - administration & dosage; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - metabolism; Gonadotropin-Releasing Hormone - pharmacology; Humans; Mice; Mice, Nude; Oxazoles - administration & dosage; Oxazoles - pharmacology; Receptors, LHRH - genetics; Receptors, LHRH - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-14-847

Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z.
69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.).
In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69).HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective.As compared to AEZS 108, the Disorazol Z - LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment.
The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.