IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides.
The insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in cellular growth, proliferation, transformation, and inhibition of apoptosis. A myriad of human cancer types have been shown to overexpress IGF-1R, including breast and pancreatic adenocarcinoma. IGF-1R signaling interferes with numerous receptor pathways, rendering tumor cells resistant to chemotherapy, anti-hormonal therapy, and epidermal growth factor receptor (EGFR, also known as HER-1) and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, (ERBB2, best known as HER-2) -targeted therapies. Targeting the IGF:IGF-1R axis with innovative peptide inhibitors and vaccine antibodies thus represents a promising therapeutic strategy to overcome drug resistance and to provide new avenues for individualized and combinatorial treatment strategies. In this study, we designed, synthesized, and characterized several B-cell epitopes from the IGF-1:IGF-1R axis. The chimeric peptide epitopes were highly immunogenic in outbred rabbits, eliciting high levels of peptide vaccine antibodies. The IGF-1R peptide antibodies and peptide mimics inhibited cell proliferation and receptor phosphorylation, induced apoptosis and antibody-dependent cellular cytotoxicity (ADCC), and significantly inhibited tumor growth in the transplantable BxPC-3 pancreatic and JIMT-1 breast cancer models. Our results showed that the peptides and antibodies targeting residues 56-81 and 233-251 are potential therapeutic and vaccine candidates for the treatment of IGF-1R-expressing cancers, including those that are resistant to the HER-2-targeted antibody, trastuzumab. Additionally, we found additive antitumor effects for the combination treatment of the IGF-1R 56-81 epitope with HER-1-418 and HER-2-597 epitopes. Treatment with the IGF-1R/HER-1 or IGF-1R/HER-2 combination inhibited proliferation, invasion, and receptor phosphorylation, and induced apoptosis and ADCC, to a greater degree than single agents.
Department of Obstetrics and Gynecology; The Ohio State University ; Columbus, OH USA.
Kevin Chu
KC
Foy
Department of Obstetrics and Gynecology; The Ohio State University ; Columbus, OH USA ; Department of Microbiology; The Ohio State University ; Columbus, OH USA.
Megan J
MJ
Miller
Department of Obstetrics and Gynecology; The Ohio State University ; Columbus, OH USA.
Jay
J
Overholser
Department of Pharmacology; Emory University ; Atlanta, GA USA.
Siobhan M
SM
Donnelly
Department of Pharmacology; Emory University ; Atlanta, GA USA.
Rita
R
Nahta
Department of Obstetrics and Gynecology; The Ohio State University ; Columbus, OH USA ; Department of Microbiology; The Ohio State University ; Columbus, OH USA ; James Cancer Hospital and Solove Research Institute and the Comprehensive Cancer Center; The Ohio State University ; Columbus, OH USA.
Pravin Tp
PT
Kaumaya
ADCC, antibody-dependent cellular cytotoxicity; EGFR/HER-1, epidermal growth factor receptor; ERBB2/HER-2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; IGF-1R, insulin-like growth factor-1 receptor; MVF, measles virus fusion protein; PBMC, peripheral blood mononuclear cell.; antibodies; epitopes; immunogenicity; peptide mimics; resistance; vaccine candidates