Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

Abstract

Abstract. In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin-releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non-vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19-31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti-GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH-based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer. IntroductionProstate cancer is the most commonly diagnosed malignancy in elderly men, and the second leading cause of cancer-associated mortality in the Western world (1,2).Standard treatments for prostate cancer include surgery, radiation therapy and androgen deprivation therapy (ADT), which are usually successful in controlling organ-confined disease. However, in 30% of patients the disease recurs and becomes androgen deprivation-resistant (3,4).Since the 1990's, gonadotropin-releasing hormone (GnRH) analogues have been the most successful drugs for achieving ADT (5). Androgen is required for the function and maintenance of prostate cancer cells, and androgen deprivation results in an inhibition of growth and decrease in volume of prostate cancer tumors (6-8). However, at advanced stages of the disease, almost all tumors develop into castration-resistant prostate cancer (CRPC), the management of which is a great challenge (6,8,9). Consequently, there is a clear requirement for improved treatments to prevent the development of CRPC, and for novel therapies to treat patients with prostate cancer.GnRH-based vaccines represent a promising anti-hormonal treatment alternative for the treatment of prostate cancer, since they reduce serum testosterone levels and avoid the flare response observed when using GnRH analogues (6,10-12). In addition, follo...

Development of a novel recombinant LHRH fusion protein for therapy of androgen and estrogen dependent cancers

“…These prevent LHRH binding to its receptors leading to suppression of the hypothalamus-pituitary-gonadal axis. LHRH based vaccines represent a promising anti-hormonal treatment alternative for the prostate cancer as they reduce serum testosterone levels (9,10,11,12) and cause atrophy of the prostate in rats and monkeys (9,13,14) by inactivation of LHRH.…”