The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

The cover for issue 2 of Oncotarget features Figure 5, "MASPIN can prevent the formation of UPA - UPA-receptor complex by a single step, and thus decrease the possibility of the abnormal degradation of the ECM, the development metastasis and angiogenesis," by Fodor, et al.

In the present study, the research team investigated AEZS-108 induced cytotoxicity and the altered mRNA expression profile of regulatory factors related to angiogenesis and metastasis in LHRH receptor-positive OCM3 cells.

Their results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in the normal uvea and UM specimens independently from the LHRH receptor-ligand interaction.

In order to investigate the mechanism of the induction of MASPIN by AEZS-108, OCM3 cells were treated with free DOX, D-Lys6 LHRH analog, or AEZS-108.

Figure 5: MASPIN can prevent the formation of UPA - UPA-receptor complex by a single step, and thus decrease the possibility of the abnormal degradation of the ECM, the development metastasis and angiogenesis. (UPA: urokinase type plasminogen activator, UPAR: UPA-receptor, HIF1A: hypoxia-inducible factor 1 alpha ECM: extracellular matrix, RAS: GTP-binding protein, RAC: subfamily of RHO-GTP-ases).

Dr. Gabor Halmos from the University of Debrecen, Department of Biopharmacy, in Debrece, Hungary as well as the Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, in Miami, FL, USA said, "Although uveal melanoma (UM) is a rare disease, it is the most prevalent lethal ophthalmological tumor."

The discovery of specific receptors for peptide hormones on cancer cells has led to the development of cytotoxic or radiolabeled hormone analogs that are appropriate for tumor localization and targeted therapy.

AEZS-108 guides the chemotherapeutic agent specifically to those tumors that express LHRH-receptors, which could result in targeted cytotoxicity and less damage to healthy tissues.

The authors reported that previously OCM3 UM cell line expresses the receptor of LHRH localized on the cell membrane and in the cytoplasm, rendering them susceptible to AEZS-108 uptake and the detection of the LHRH receptor in OCM3 cells has led to the use of AEZS-108 for targeted therapy of the tumor.

Moreover, that the OCM3 UM cell line expresses the LHRH receptor and LHRH rendering them susceptible to AEZS-108 uptake.

The Halmos Research Team concluded, "In summary, our data confirmed previous results showing LHRH receptor expression in OCM3 cells, a UM in vitro model. Furthermore, we report for the first time that AEZS-108 causes changes in the expression of genes that are involved in angiogenesis and ECM degradation and which might inhibit cell proliferation and induce apoptosis in OCM3 cells.

These findings suggest that AEZS-108 plays a pivotal role in the regulation of angiogenesis and tumor suppression. Taken together, targeted cytotoxic LHRH analogs, such as AEZS-108, might serve as an effective treatment for patients with LHRH receptor-positive uveal melanoma."

Full text - https://doi.org/10.18632/oncotarget.27431

Correspondence to - Gabor Halmos - halmos.gabor@pharm.unideb.hu

Keywords - uveal melanoma, luteinizing hormone-releasing hormone (LHRH) receptor, angiogenesis, MASPIN/SERPINB5, AEZS-108 (AN-152/Zoptarelin Doxorubicin Acetate)