title: A new look at drugs targeting malignant melanoma--an application for mass spectrometry imaging.
abstract: Malignant melanoma (MM) patients are being treated with an increasing number of personalized medicine (PM) drugs, several of which are small molecule drugs developed to treat patients with specific disease genotypes and phenotypes. In particular, the clinical application of protein kinase inhibitors has been highly effective for certain subsets of MM patients. Vemurafenib, a protein kinase inhibitor targeting BRAF-mutated protein, has shown significant efficacy in slowing disease progression. In this paper, we provide an overview of this new generation of targeted drugs, and demonstrate the first data on localization of PM drugs within tumor compartments. In this study, we have introduced MALDI-MS imaging to provide new information on one of the drugs currently used in the PM treatment of MM, vemurafenib. In a proof-of-concept in vitro study, MALDI-MS imaging was used to identify vemurafenib applied to metastatic lymph nodes tumors of subjects attending the regional hospital network of Southern Sweden. The paper provides evidence of BRAF overexpression in tumors isolated from MM patients and localization of the specific drug targeting BRAF, vemurafenib, using MS fragment ion signatures. Our ability to determine drug uptake at the target sites of directed therapy provides important opportunity for increasing our understanding about the mode of action of drug activity within the disease environment.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sugihara
authors.forename: Akos
authors.initials: A
authors.lastname: Végvári
authors.forename: Charlotte
authors.initials: C
authors.lastname: Welinder
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.forename: Lotta
authors.initials: L
authors.lastname: Lundgren
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Breslin
authors.forename: Elisabet
authors.initials: E
authors.lastname: Wieslander
authors.forename: Thomas
authors.initials: T
authors.lastname: Laurell
authors.forename: Melinda
authors.initials: M
authors.lastname: Rezeli
authors.forename: Bo
authors.initials: B
authors.lastname: Jansson
authors.forename: Toshihide
authors.initials: T
authors.lastname: Nishimura
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Fehniger
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.forename: György
authors.initials: G
authors.lastname: Marko-Varga
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D008545:Melanoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D057054:Molecular Imaging / Q000379:methods*; D057285:Precision Medicine / Q000379:methods*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Biomedicine; Clinical studies; Malignant melanoma; Mass spectrometry imaging; Personalized medicine; Protein sequencing