Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients
The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. HOXB9 expression and activation were measured in eight...
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| Veröffentlicht in: | Clinical cancer research Jg. 23; H. 15; S. 4312 - 4322 |
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01.08.2017
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| Abstract | The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab.
HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test.
HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (
< 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006-4.125;
= 0.048).
These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy.
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| AbstractList | Purpose: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab.Experimental Design: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test.Results: HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (P < 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006-4.125; P = 0.048).Conclusions: These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy. Clin Cancer Res; 23(15); 4312-22. ©2017 AACR. The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test. HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly ( < 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006-4.125; = 0.048). These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy. . |
| Author | Cremolini, Chiara Santoro, Raffaela Piro, Geny Ligorio, Francesca Merz, Valeria Loupakis, Fotios Zanotto, Marco Carbone, Carmine Simionato, Francesca Di Nicolantonio, Federica Bardelli, Alberto Alì, Greta Melisi, Davide Zecchetto, Camilla Rossini, Daniele Fontanini, Gabriella Tortora, Giampaolo |
| Author_xml | – sequence: 1 givenname: Carmine surname: Carbone fullname: Carbone, Carmine organization: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy – sequence: 2 givenname: Geny surname: Piro fullname: Piro, Geny organization: Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy – sequence: 3 givenname: Francesca surname: Simionato fullname: Simionato, Francesca organization: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – sequence: 4 givenname: Francesca surname: Ligorio fullname: Ligorio, Francesca organization: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy – sequence: 5 givenname: Chiara surname: Cremolini fullname: Cremolini, Chiara organization: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy – sequence: 6 givenname: Fotios surname: Loupakis fullname: Loupakis, Fotios organization: Unit of Oncology 1, Istituto Oncologico Veneto IRCCS, Padova, Italy – sequence: 7 givenname: Greta surname: Alì fullname: Alì, Greta organization: Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy – sequence: 8 givenname: Daniele surname: Rossini fullname: Rossini, Daniele organization: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy – sequence: 9 givenname: Valeria surname: Merz fullname: Merz, Valeria organization: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – sequence: 10 givenname: Raffaela surname: Santoro fullname: Santoro, Raffaela organization: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy – sequence: 11 givenname: Camilla surname: Zecchetto fullname: Zecchetto, Camilla organization: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – sequence: 12 givenname: Marco surname: Zanotto fullname: Zanotto, Marco organization: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy – sequence: 13 givenname: Federica surname: Di Nicolantonio fullname: Di Nicolantonio, Federica organization: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy – sequence: 14 givenname: Alberto surname: Bardelli fullname: Bardelli, Alberto organization: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy – sequence: 15 givenname: Gabriella surname: Fontanini fullname: Fontanini, Gabriella organization: Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy – sequence: 16 givenname: Giampaolo surname: Tortora fullname: Tortora, Giampaolo organization: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – sequence: 17 givenname: Davide surname: Melisi fullname: Melisi, Davide email: davide.melisi@univr.it organization: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy |
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| SubjectTerms | Adult Aged Angiopoietin-like Proteins - blood Animals Bevacizumab - administration & dosage Cell Line, Tumor Chemokine CXCL1 - blood Colorectal Neoplasms - blood Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Disease-Free Survival Drug Resistance, Neoplasm - genetics Female Gene Expression Regulation, Neoplastic - drug effects Homeodomain Proteins - genetics Humans Interleukin-8 - blood Male Mice Middle Aged Neoplasm Metastasis Prognosis Transforming Growth Factor beta - blood Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - genetics |
| Title | Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients |
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