title: Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma.
abstract: BACKGROUND
  Clinical studies implying the sunitinib multi-kinase inhibitor have led to disappointing results for breast cancer care but mostly focused on HER2-negative subtypes. Preclinical researches involving this drug mostly concern Triple Negative Breast Cancer (TNBC) murine models. Here, we explored the therapeutic efficacy of sunitinib on a PyMT-derived transplanted model classified as luminal B (HER2-positive) and monitored the response to treatment using both in vivo and ex vivo approaches.
  
  
  METHODS
  Tumour-induced animals were treated for 9 (n = 7) or 14 (n = 8) days with sunitinib at 40 mg/kg or with vehicle only. Response to therapy was assessed in vivo by monitoring glucose tumour metabolism and hypoxia using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and [(18)F]fluoromisonidazole ([(18)F]FMISO) Positron Emission Tomography (PET). After primary tumour excision, ex vivo digital microscopy was performed on treated and control samples to estimate vascular density (CD31), apoptosis (Tunel), proliferation (Ki-67), Tumour-Associated Macrophage (TAM) infiltration (F4/80), metabolism (GLUT1) and cellular response to hypoxia (HIF1 alpha). The drug impact on the metastasis rate was evaluated by monitoring the PyMT gene expression in the lungs of the treated and control groups.
  
  
  RESULTS
  Concomitant with sunitinib-induced tumour size regression, [(18)F]FDG PET imaging showed a stable glycolysis-related metabolism inside tumours undergoing treatment compared to an increased metabolism in untreated tumours, resulting at treatment end in 1.5 less [(18)F]FDG uptake in treated (n = 4) vs control (n = 3) tumours (p < 0.05). With this small sample, [(18)F]FMISO PET showed a non-significant decrease of hypoxia in treated vs control tumours. The drug triggered a 4.9 fold vascular volume regression (p < 0.05), as well as a 17.7 fold induction of tumour cell apoptosis (p < 0.001). The hypoxia induced factor 1 alpha (HIF1 alpha) expression was twice lower in the treated group than in the control group (p < 0.05). Moreover, the occurrence of lung metastases was not reduced by the drug.
  
  
  CONCLUSIONS
  [(18)F]FDG and [(18)F]FMISO PET were relevant approaches to study the response to sunitinib in this luminal B (HER2-positive) model. The sunitinib-induced vascular network shrinkage did not significantly increase tumour hypoxia, suggesting that tumour regression was mainly due to the pro-apoptotic properties of the drug. Sunitinib did not inhibit the metastatic process in this PyMT transplanted model.
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. benoit.theze@cea.fr.
authors.forename: Benoît
authors.initials: B
authors.lastname: Thézé
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. nicholas.bernards@googlemail.com.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bernards
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. audrey.beynel@gmail.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Beynel
authors.affiliation: Animal Genetics and Integrative Biology, INRA-AgroParisTech, UMR 1313, Jouy-en-Josas, France. bouet.stephan@sfr.fr.|Laboratory of Radiobiology and Genomics Studies, CEA, DSV, IRCM, SREIT, Jouy-en-Josas, France. bouet.stephan@sfr.fr.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bouet
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. bertrand.kuhnast@cea.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. irene.buvat@cea.fr.
authors.forename: Irène
authors.initials: I
authors.lastname: Buvat
authors.affiliation: Inserm U970, Université Paris Descartes, Paris, France. bertrand.tavitian@inserm.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tavitian
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV, UMR 1023 Inserm/CEA/Université Paris Sud - ERL 9218 CNRS, CEA/I²BM/SHFJ, 4 place du Général Leclerc, 91400, Orsay, France. raphael.boisgard@cea.fr.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; C495678:Slc2a1 protein, mouse; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; D008920:Misonidazole; D000077210:Sunitinib