title: Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients.
abstract: 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.
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Carbone
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.|Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy.
authors.forename: Geny
authors.initials: G
authors.lastname: Piro
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Simionato
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ligorio
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Unit of Oncology 1, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Alì
authors.affiliation: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Rossini
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Merz
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Santoro
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Zecchetto
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Zanotto
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy.|Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy. davide.melisi@univr.it.|Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
mesh_terms: D000328:Adult; D000368:Aged; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins / Q000097:blood; D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; C485793:Angptl2 protein, mouse; D054360:Chemokine CXCL1; C491257:HOXB9 protein, human; D018398:Homeodomain Proteins; D016209:Interleukin-8; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab