Targeted cancer therapy with gonadotropin-releasing hormone chimeric proteins

Abstract

Tumor-associated antigens (TAAs) have been identified mainly to determine cancer prognosis. In the past few years, TAAs have been used in the development of treatment modalities such as tumor vaccination. This review describes an additional application of TAAs: as a target for specific antitumor treatment. Since TAAs are overexpressed on the tumor cell surface, they can be targeted to deliver drugs directly to cancer cells. One such delivery system exploits chimeric proteins. Chimeric proteins are a class of targeted molecules designed to recognize and specifically destroy cells that overexpress specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both cell-targeting and cell-killing moieties. The authors' laboratory has developed a number of chimeric proteins using gonadotropin-releasing hormone (GnRH) as the targeting moiety. These chimeras recognize a GnRH binding site that is expressed on adenocarcinoma cells. GnRH was fused to a large number of killing moieties, including bacterial and human proapoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing chimeric proteins for targeted therapy represents a new and exciting therapeutic modality for the treatment of cancer in humans.

Expression of Receptors for Luteinizing Hormone-Releasing Hormone (LH-RH) in Prostate Cancers following Therapy with LH-RH Agonists

“…A potential therapeutic target is the LH-RH receptor. Recent studies have shown that LH-RH receptors are expressed on a variety of human cancer cells, including ovarian (10), endometrial (11), pancreatic (12), rectal (13), renal (14), bladder (15), and breast cancer cells (16). Several groups have also shown LH-RH receptor expression with fairly high prevalence in prostate cancer cells.…”

Recombinant, refolded tetrameric p53 and gonadotropin-releasing hormone-p53 slow proliferation and induce apoptosis in p53-deficient cancer cells

“…Therefore, this strategy would allow targeting of a p53 protein therapeutic to tumors in these hormone-responsive tissue types. A GnRH fusion with the 66-kDa Pseudomonas exotoxin protein resulted in growth inhibition and killing in a wide variety of hormone-responsive cancer cell lines, including ovarian and breast cancer lines (42,43). The fused GnRH peptide also efficiently delivered Pokeweed antiviral protein (44) and proapoptotic proteins Bik, Bax, Bak (45), and DFF40 (46) to several adenocarcinoma cell lines where they were able to significantly inhibit growth.…”

Human Malignant Melanomas Express Receptors for Luteinizing Hormone Releasing Hormone Allowing Targeted Therapy with Cytotoxic Luteinizing Hormone Releasing Hormone Analogue

“…Although LHRH receptors were found on cells of healthy reproductive organs, they are absent or only marginally expressed in other normal tissues (24). Interestingly, binding sites for LHRH were also detected in human tumor specimens and cancer cell lines originating from the liver, larynx, kidney, pancreas, colon, and brain (25)(26)(27)(28)(29). In addition, the presence of LHRH receptors was reported recently in two human melanoma cell lines (30).…”