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. |
Other formats:
BibTeX
LaTeX
RIS
@article{1300089, author = {Zanella, Eugenia R. and Galimi, Francesco and Sassi, Francesco and Migliardi, Giorgia and Cottino, Francesca and Leto, Simonetta M. and Lupo, Barbara and Erriquez, Jessica and Isella, Claudio and Comoglio, Paolo M. and Medico, Enzo and Tejpar, Sabine and Budinská, Eva and Trusolino, Livio and Bertotti, Andrea}, article_location = {WASHINGTON}, article_number = {272}, doi = {http://dx.doi.org/10.1126/scitranslmed.3010445}, keywords = {epidermal growth factor receptor; colorectal cancer}, language = {eng}, issn = {1946-6234}, journal = {SCIENCE TRANSLATIONAL MEDICINE}, title = {IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies}, volume = {7}, year = {2015} }
TY - JOUR ID - 1300089 AU - Zanella, Eugenia R. - Galimi, Francesco - Sassi, Francesco - Migliardi, Giorgia - Cottino, Francesca - Leto, Simonetta M. - Lupo, Barbara - Erriquez, Jessica - Isella, Claudio - Comoglio, Paolo M. - Medico, Enzo - Tejpar, Sabine - Budinská, Eva - Trusolino, Livio - Bertotti, Andrea PY - 2015 TI - IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies JF - SCIENCE TRANSLATIONAL MEDICINE VL - 7 IS - 272 SP - "272ra12" EP - "272ra12" PB - AMER ASSOC ADVANCEMENT SCIENCE SN - 19466234 KW - epidermal growth factor receptor KW - colorectal cancer N2 - 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. ER -
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. \textit{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.
|