Specific Antibodies Elicited by a Novel DNA Vaccine Targeting Gastrin-Releasing Peptide Inhibit Murine Melanoma Growth In Vivo

Abstract

The elevated expression and receptor binding of gastrin-releasing peptide (GRP) in various types of cancer, especially in malignant melanoma of the skin, suggest that GRP might be a putative target for immunotherapy in neoplastic diseases. We have therefore constructed a novel DNA vaccine coding for six tandem repeats of a fragment of GRP from amino acids 18 to 27 (GRP6) flanked by helper T-cell epitopes for increased immunogenicity, including HSP65, a tetanus toxoid fragment from amino acids 830 to 844 (T), pan-HLA-DR-binding epitope (

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…Silencing of GRPR/GRP by siRNA-delivery has been shown to decrease the signaling cascades leading to proliferation and the growth of neuroblastomas[39], ovarian-cancers[35] and lung-cancers[46]. Another novel approach reported to be effective[47] in silencing the autocrine-growth effect of Bn-related peptides is to immunize animals containing melanomas which possess GRPR and produce GRP, with a DNA-vaccine contain GRP-fragments coupled to tetanus-toxoid and helper-T cell epitopes. Administration intramuscularly of this vaccine decreased B16-F10 melanoma lung invasion and tumor associated angiogenesis[47].…”

Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

“…Recent data indicate that angiogenesis is not only essential for rapidly growing macroscopic tumors, but also contributes to the micro-scopic premalignant phase of neoplastic progression, further cementing its status as an integral hallmark of cancer[40]. A novel DNA vaccine targeting GRP significantly reduced tumor-associated angiogenesis and vascularization of intradermal tumors of C57BL/6 mouse-derived B16 melanoma cells (B16- F10)[41]. GRP has been reported to stimulate GPR receptor-induced pro-angiogenic gene expression as well as the expression of various angiogenic markers, including platelet-endothelial cell adhesion molecule (PECAM-1) and vascular endothelial growth factor (VEGF)[35],[41].…”

“…A novel DNA vaccine targeting GRP significantly reduced tumor-associated angiogenesis and vascularization of intradermal tumors of C57BL/6 mouse-derived B16 melanoma cells (B16- F10)[41]. GRP has been reported to stimulate GPR receptor-induced pro-angiogenic gene expression as well as the expression of various angiogenic markers, including platelet-endothelial cell adhesion molecule (PECAM-1) and vascular endothelial growth factor (VEGF)[35],[41]. High titers of GRP-specific Abs could neutralize elevated levels of the GRP self-peptide made by tumor cells and block the GRP/GRPR autocrine loop of GRP-dependent tumors.…”

DNA Vaccination: Using the Patient′s Immune System to Overcome Cancer

“…Particular success was reported for xenogeneic strategies, viral delivery systems, and the use of IL-2 as an adjuvant [ 101 ]. In mouse models, efficacy of DNA vaccines encoding for all known melanoma-associated antigens was reported including gp100 (melanocyte protein 17/Pmel-17), GRP (gastrin-releasing peptide) [ 102 ], MAGE-1 (melanoma-associated antigen) [ 103 ], MART-1, MUC-18/MCAM [ 104 ], TRP-1 (tyrosinase-related protein-1/gp75), TRP-2, or tyrosinase. Also inhibitor of apoptosis proteins (IAPs) like ML-IAP (melanoma inhibitor of apoptosis protein) [ 105 ] and survivin [ 106 ] were used.…”