title: Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies.
abstract: Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fazenbaker
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Breen
authors.affiliation: Translational Science, MedImmune, Gaithersburg, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Translational Science, MedImmune, Gaithersburg, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.affiliation: Biostatistics, MedImmune, Gaithersburg, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ren
authors.affiliation: Translational Science, MedImmune, Gaithersburg, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, MD, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II