Targeting of Peptide Cytotoxins to LHRH Receptors For Treatment of Cancer

Abstract

Receptors for LHRH (luteinizing hormone-releasing hormone) are expressed in about 80% of human endometrial, ovarian and prostate cancers and are also found in more than 50% of breast cancers including triple negative breast cancers. In the human body, LHRH receptors are found at significant levels in the pituitary and reproductive organs. Other benign tissues or hematopoietic stem cells express only low levels of receptors for LHRH or no receptors. Thus LHRH receptors are promising targets for a receptor- mediated chemotherapy with cytotoxic hybrid molecules. Cytotoxic analogs of LHRH consist of a LHRH agonist, which is used as a carrier peptide and DOX or its derivatives. Cytotoxic analogs of LHRH, AEZS-108 (formerly known as AN-152) and AN-207, exhibit anti-cancer activity in various in vitro and in vivo models of LHRH-receptor positive cancers. In AEZS-108 (zoptarelin DOX) DOX is covalently linked to the LHRH agonist [D-Lys(6)]LHRH. Results of phase I and II clinical studies in patients with breast, endometrial and ovarian cancers demonstrated good anticancer activity with moderate toxic side effects and without any sign of cardiotoxicity so far. AEZS-108 is also being evaluated in phase I/II studies in castration resistant prostate cancer and metastatic bladder cancer. Because of the very promising phase II results in endometrial cancer, a multinational, multicenter phase III study of this malignancy has been initiated and is currently recruiting patients.

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

“…These results might be explained by the fact, established previously, that some cytotoxic ligand analogs containing DOX show ten times lower antiproliferative activity in vitro than doxorubicin. However, in vivo experiments are in accord with the in vitro results and demonstrate that cytotoxic ligand analogs present high antitumor activity, greater efficacy and less toxicity than doxorubicin [7][8][9]32].…”

“…Oncotarget 176 www.oncotarget.com Numerous preclinical studies have demonstrated the efficacy of chemotherapy based on cytotoxic peptide conjugates targeted to receptors on different tumors [6][7][8][9][10]. Clinical trials confirmed that targeted cytotoxic LHRH analog can improve the effectiveness of treatment and reduce general side effects [11][12][13].…”

“…AEZS-108 (formerly known as AN-152 / INN: Zoptarelin Doxorubicin Acetate) is a targeted cytotoxic LHRH-analog consisting of doxorubicin conjugated to D-Lys 6 LHRH. 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 [9,11,13,30,32]. AEZS-108 has been utilized in phase III clinical trials in advanced, recurrent or metastatic endometrial cancer, in phase I-II in castration resistant prostate cancer and ovarian cancer [9,11,13,32].…”

Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

“…Cytotoxic GnRH agonist Zoptarelin Doxorubicin is an effective therapeutic agent for the treatment of GnRH receptor‐positive breast cancers . Glycolysis inhibitor 2DG, a compound which targets a primary source of cell energy of cancer cells, induces apoptotic cell death in different cancers .…”

“…Cytotoxic GnRH agonist Zoptarelin Doxorubicin is an effective therapeutic agent for the treatment of GnRH receptor-positive breast cancers. 5,[18][19][20][21][22][23][24] Glycolysis inhibitor 2DG, a compound which targets a primary source of cell energy of cancer cells, induces apoptotic cell death in different cancers. [9][10][11][12][13] In this study, we have analyzed whether the effectiveness of the GnRH receptor-mediated chemotherapy using Zoptarelin Doxorubicin in triple-negative breast cancer (TNBC) cells can be strengthened by co-treatment with 2DG in vitro and in vivo.…”