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

BACKGROUND: 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. METHODS: 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.). RESULTS: 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. CONCLUSION: 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.

Macrophage migration-inhibitory factor levels in serum of patients with ovarian cancer correlates with poor prognosis.

Ovarian cancer is generally thought of as a cancer with poor prognosis. However, prognostic appraisal of the disease is based on tumor stages, surgical features or sensibility towards platinum-based chemotherapy. There are data that also grant immunological parameters such as CD8(+) T-lymphocyte-(CD8 T-cell) infiltration in tumor tissue, a prognostic role. Macrophage migration-inhibitory factor (MIF) has been described as a tumor-derived protein which allows tumor cell immune escape from antitumoral host natural killer (NK) - and CD8 T-cells. This immune escape is functionally based on down-regulation of the receptor natural killer group 2D (NKG2D). We here report that the levels of the MIF protein which is known to be secreted in ascites and serum of patients with ovarian cancer, not only seems to correlate with common prognostic parameters such as tumor stage or platinum sensitivity, but also with CD8 T- and NK-cell infiltration in tumor tissue. We therefore believe that MIF may play a suppressive role in the host antitumor immune response, which may have a negative impact on the course of the disease. The fact that MIF levels in serum of patients at primary diagnosis correlate with platinum sensibility supports the hypothesis that serum MIF levels should be evaluated as a parameter reflecting tumor sensibility towards chemotherapy in early stages of the disease.