Targeting of Peptide Cytotoxins to LHRH Receptors For Treatment of Cancer

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.