title: A novel technique of serial biopsy in mouse brain tumour models.
abstract: Biopsy is often used to investigate brain tumour-specific abnormalities so that treatments can be appropriately tailored. Dacomitinib (PF-00299804) is a tyrosine kinase inhibitor (TKI), which is predicted to only be effective in cancers where the targets of this drug (EGFR, ERBB2, ERBB4) are abnormally active. Here we describe a method by which serial biopsy can be used to validate response to dacomitinib treatment in vivo using a mouse glioblastoma model. In order to determine the feasibility of conducting serial brain biopsies in mouse models with minimal morbidity, and if successful, investigate whether this can facilitate evaluation of chemotherapeutic response, an orthotopic model of glioblastoma was used. Immunodeficient mice received cortical implants of the human glioblastoma cell line, U87MG, modified to express the constitutively-active EGFR mutant, EGFRvIII, GFP and luciferase. Tumour growth was monitored using bioluminescence imaging. Upon attainment of a moderate tumour size, free-hand biopsy was performed on a subgroup of animals. Animal monitoring using a neurological severity score (NSS) showed that all mice survived the procedure with minimal perioperative morbidity and recovered to similar levels as controls over a period of five days. The technique was used to evaluate dacomitinib-mediated inhibition of EGFRvIII two hours after drug administration. We show that serial tissue samples can be obtained, that the samples retain histological features of the tumour, and are of sufficient quality to determine response to treatment. This approach represents a significant advance in murine brain surgery that may be applicable to other brain tumour models. Importantly, the methodology has the potential to accelerate the preclinical in vivo drug screening process.
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.|Department of Neurosurgery, Princess Margaret Hospital, Perth, WA, Australia.
authors.forename: Sasha
authors.identifier: http://orcid.org/0000-0001-9052-0787
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
authors.forename: Hilary
authors.initials: H
authors.lastname: Hii
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.
authors.forename: Joel
authors.initials: J
authors.lastname: Huang
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
authors.forename: Mathew
authors.initials: M
authors.lastname: Ancliffe
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Department of Oncology, Princess Margaret Hospital, Perth, WA, Australia.
authors.forename: Nick G
authors.initials: NG
authors.lastname: Gottardo
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Dallas
authors.affiliation: Department of Neurosurgery, Princess Margaret Hospital, Perth, WA, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Telethon Kids Institute, Perth, WA, Australia.|Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
authors.forename: Raelene
authors.initials: R
authors.lastname: Endersby
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy / Q000379:methods*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D012720:Severity of Illness Index; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; C525726:dacomitinib