ZANELLA, Eugenia R., Francesco GALIMI, Francesco SASSI, Giorgia MIGLIARDI, Francesca COTTINO, Simonetta M. LETO, Barbara LUPO, Jessica ERRIQUEZ, Claudio ISELLA, Paolo M. COMOGLIO, Enzo MEDICO, Sabine TEJPAR, Eva BUDINSKÁ, Livio TRUSOLINO and Andrea BERTOTTI. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies. SCIENCE TRANSLATIONAL MEDICINE. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2015, vol. 7, No 272, p. "272ra12", 13 pp. ISSN 1946-6234. Available from: https://dx.doi.org/10.1126/scitranslmed.3010445.
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Basic information
Original name IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies
Authors ZANELLA, Eugenia R. (380 Italy), Francesco GALIMI (380 Italy), Francesco SASSI (380 Italy), Giorgia MIGLIARDI (380 Italy), Francesca COTTINO (380 Italy), Simonetta M. LETO (380 Italy), Barbara LUPO (380 Italy), Jessica ERRIQUEZ (380 Italy), Claudio ISELLA (380 Italy), Paolo M. COMOGLIO (380 Italy), Enzo MEDICO (380 Italy), Sabine TEJPAR (56 Belgium), Eva BUDINSKÁ (703 Slovakia, guarantor, belonging to the institution), Livio TRUSOLINO (380 Italy) and Andrea BERTOTTI (380 Italy).
Edition SCIENCE TRANSLATIONAL MEDICINE, WASHINGTON, AMER ASSOC ADVANCEMENT SCIENCE, 2015, 1946-6234.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30200 3.2 Clinical medicine
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 16.264
RIV identification code RIV/00216224:14110/15:00082980
Organization unit Faculty of Medicine
Doi http://dx.doi.org/10.1126/scitranslmed.3010445
UT WoS 000349422700005
Keywords in English epidermal growth factor receptor; colorectal cancer
Tags EL OK
Tags International impact, Reviewed
Changed by Changed by: Soňa Böhmová, učo 232884. Changed: 27/5/2015 14:21.
Abstract
Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations. Samples from xenopatients that responded to cetuximab, an anti-EGFR agent, with disease stabilization displayed high levels of EGFR family ligands and receptors, indicating high EGFR pathway activity. Five of 21 SD models (23.8%) characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small-molecule inhibitor. In addition, a subset of cases in which enhanced EGFR inhibition was unproductive (6 of 16, 37.5%) exhibited marked overexpression of insulin-like growth factor 2 (IGF2). Enrichment of IGF2 overexpressors among cases with SD was demonstrated in the entire xenopatient collection and was confirmed in patients by mining clinical gene expression data sets. In functional studies, IGF2 overproduction attenuated the efficacy of cetuximab. Conversely, interception of IGF2-dependent signaling in IGF2-overexpressing xenopatients potentiated the effects of cetuximab. The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.
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