title: Masitinib (AB1010), from canine tumor model to human clinical development: where we are?
abstract: Masitinib mesylate (AB1010) is a novel potent and selective tyrosine kinase inhibitor, targeting mainly wild-type and mutated c-Kit receptor (c-KitR), Platelet Derived Growth Factor Receptor-alfa/beta (PDGFRa/ß), Lymphocyte-specific kinase (Lck), Lck/Yes-related protein (LYn), Fibroblast Growth Factor Receptor 3 (FGFR3) and Focal Adhesion Kinase (FAK). It is the first anticancer therapy approved in veterinary medicine for the treatment of unresectable canine mast cell tumors (CMCTs), harboring activating c-KitR mutations, at dose of 12.5mg/kg once daily. Considering its anti-proliferative action, principally given by inhibiting the MCs c-KitR anti-angiogenic pathway that leads cancer progression, and its role as chemosensitizer, masitinib is under clinical investigation in several human malignancies (Gastro-Intestinal Stromal Tumors, acute myeloid leukemia, systemic mastocytosis, pancreatic cancer, multiple myeloma, non-small cell lung cancer, melanoma, ovarian and prostate cancer), which are characterized by similar canine c-KIT proto-oncogene mutations. Here, we analyze masitinib structure activity, its pharmacokinetics compared to imatinib, the c-KitR pathway referring to the most frequent c-KIT mutations sensitive or resistant to this novel drug compared to imatinib, and masitinib safety profile. We, also, explore preclinical and clinical (completed and ongoing) trials with the aim to emphasize as this recent anti-angiogenic therapy, at first approved in CMCTs and, currently in development for the treatment of several human neoplasms, could be represent a milestone in translational oncology, in which the murine experimental model of cancer research could be integrated by canine spontaneous tumor model.
authors.affiliation: Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marech
authors.affiliation: Department of Prevention and Animal Health, ASL BAT, Barletta, Bari, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Patruno
authors.affiliation: Chair of Pathology, Veterinary Medical School, University of Bari, Valenzano, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zizzo
authors.affiliation: Chair of Pathology, Veterinary Medical School, University of Bari, Valenzano, Bari, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gadaleta
authors.affiliation: Chair of Pathology, Veterinary Medical School, University of Bari, Valenzano, Bari, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Introna
authors.affiliation: Pathology Unit, ASL BA, Bari, Italy.
authors.forename: Alfredo Francesco
authors.initials: AF
authors.lastname: Zito
authors.affiliation: Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.
authors.forename: Cosmo Damiano
authors.initials: CD
authors.lastname: Gadaleta
authors.affiliation: Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. Electronic address: giroran@tiscalinet.it.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Ranieri
mesh_terms: D000818:Animals; D001549:Benzamides; D004285:Dogs; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; C000715470:MAS1 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D013844:Thiazoles; C526575:masitinib
keywords: Canine tumor model; Dog mast cell tumors; Gastro-Intestinal Stromal Tumors; Masitinib; Pancreatic cancer; Systemic mastocytosis; c-Kit receptor