title: Vandetanib as a potential new treatment for estrogen receptor-negative breast cancers.
abstract: The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers (BC) but its role in estrogen receptor (ER) negative tumors is unknown. Here we investigated the expression of RET in breast cancer patients tumors and patient-derived xenografts (PDX) and evaluated the therapeutic potential of Vandetanib, a tyrosin kinase inhibitor with strong activity against RET, EGFR and VEGFR2, in ER negative breast cancer PDX. The RT-PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX, showed elevated levels of RET in ER+ and HER2+ subtypes and in a small subgroup of triple-negative breast cancers (TNBC). The activity of Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER2+ BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in PDX models with high expression of RET or EGFR. The effect was associated with inhibition of RET/EGFR phosphorylation and MAP kinase pathway and increased necrosis. In a PDX model with no expression of RET nor EGFR, Vandetanib slowed tumor growth without inducing tumor regression. In addition, treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested, suggesting inhibition of tumor vascularization. In summary, these preclinical results suggest that Vandetanib treatment could be useful for patients with ER negative breast cancers overexpressing Vandetanib's main targets.
authors.affiliation: Genetics Department, Hospital, Institut Curie, Paris, 75005, France.|Faculty of Pharmacy, Aleppo University, Aleppo, Syria.
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.affiliation: Translational Research Department, Institut Curie, Paris, 75005, France.
authors.forename: Dalila
authors.initials: D
authors.lastname: Labiod
authors.affiliation: BioPôle Alfort, National Veterinary School of Alfort, 7, Av. Du Général De Gaulle, 94704, Maisons Alfort, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Château-Joubert
authors.affiliation: Translational Research Department, Institut Curie, Paris, 75005, France.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: de Plater
authors.affiliation: Translational Research Department, Institut Curie, Paris, 75005, France.
authors.forename: Rania
authors.initials: R
authors.lastname: El Botty
authors.affiliation: Genetics Department, Hospital, Institut Curie, Paris, 75005, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: Genetics Department, Hospital, Institut Curie, Paris, 75005, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Bonin
authors.affiliation: BioPôle Alfort, National Veterinary School of Alfort, 7, Av. Du Général De Gaulle, 94704, Maisons Alfort, France.|PHASE Department, INRA, Nouzilly, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Servely
authors.affiliation: Medical Oncology Department, Institut Curie, Paris, 75005, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dieras
authors.affiliation: Genetics Department, Hospital, Institut Curie, Paris, 75005, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Translational Research Department, Institut Curie, Paris, 75005, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D051096:Proto-Oncogene Proteins c-ret; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib
keywords: PDX models; RET; breast cancer; vandetanib