title: Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models.
abstract: Resistance to anti-angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short-term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long-term anti-VEGF monoclonal antibody therapy in several well-validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti-VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short- nor long-term exposure to anti-VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up-regulation of the hypoxia marker GLUT1 in PNETs, whereas anti-VEGF did not. These results indicate that anti-VEGF mediates anti-tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context-dependent manner and are mechanistically distinct from one another.
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA. msingh@gene.com
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.forename: Suzana S
authors.initials: SS
authors.lastname: Couto
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Anthony
authors.initials: A
authors.lastname: Lima
authors.forename: Jason H
authors.initials: JH
authors.lastname: Cheng
authors.forename: Rafael
authors.initials: R
authors.lastname: Molina
authors.forename: Jason E
authors.initials: JE
authors.lastname: Long
authors.forename: Patricia
authors.initials: P
authors.lastname: Hamilton
authors.forename: Angela
authors.initials: A
authors.lastname: McNutt
authors.forename: Ian
authors.initials: I
authors.lastname: Kasman
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Nannini
authors.forename: Hani Bou
authors.initials: HB
authors.lastname: Reslan
authors.forename: Tim C
authors.initials: TC
authors.lastname: Cao
authors.forename: Calvin C K
authors.initials: CC
authors.lastname: Ho
authors.forename: Kai H
authors.initials: KH
authors.lastname: Barck
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Leisa
authors.initials: L
authors.lastname: Johnson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005818:Genetic Engineering; D007211:Indoles / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011758:Pyrroles / Q000627:therapeutic use; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D020533:Angiogenesis Inhibitors; D000888:Antibodies, Anti-Idiotypic; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000077210:Sunitinib