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Biopsy is often used to investigate brain tumour-specific abnormalities so that treatments can be appropriately tailored. Bangladesh National Building Code 2010. 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. Introduction Brain biopsy is a commonly used clinical procedure that facilitates extraction of brain tissue for histological analysis [], and the subsequent initiation of appropriate treatment based on accurate morphological diagnosis []. Lianja App Builder Serial Number. Recent advances in genomic profiling techniques have enabled rapid identification of mutations and signalling pathway deregulation leading to a paradigm shift in the way that tumours are defined. Traditional histological analysis of tumours is being superseded by molecular profiling [],[], providing a platform for the development of “targeted therapies” [] and individually tailored treatment protocols that optimise patient outcomes while minimizing side effects. Over recent years, mouse models have been indispensable for modelling rare human tumours. Sophisticated techniques have been developed to generate tumours driven by specific aberrant pathways known to be associated with tumour subtypes [].

Translating biopsy techniques to the preclinical setting has the potential to provide evidence of response to treatment with novel chemotherapeutic agents. Immunohistological analysis remains the gold standard to identify deregulated signalling pathways and changes in protein expression that may occur within a tumour in response to treatment. However, needle biopsy is largely impractical in mouse models due to the size of traditional biopsy tools relative to murine tissues, and ex vivo histological analysis and live animal imaging are more commonly used in this context. Although the sophisticated tools and techniques that have been developed to assess the deregulation of specific genes/pathways are useful for longitudinal in vivo studies of brain diseases, these methods are generally limited to inducible models designed to express specific reporters [,]. The traditional alternative involves standard histological techniques that involve tissue harvesting; a process which is not only time consuming and involves a large number of animals, but also relies on assumptions of similarity between animals for histological comparison. A major goal of preclinical research is to determine if novel oncological therapies are effective in different cancer models.

Receptor tyrosine kinase (RTK) inhibitors are frequently being developed for cancer therapy. In order to determine if these agents are efficacious, it is imperative to first ensure that the drug is able to inhibit its intended target in vivo. U87MG is a widely used model of human GBM, and its rapid growth in mouse brain is ideally suited for preclinical research. The model we developed utilised the U87MG cell line which was modified to express the EGFRvIII mutation that is found in up to 50% of human GBM.