Genetically Engineered Mouse

About: Genetically Engineered Mouse is a research topic. Over the lifetime, 499 publications have been published within this topic receiving 16571 citations.

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Abstract: Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-alpha mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography-computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.

The mighty mouse: genetically engineered mouse models in cancer drug development

Abstract: Deficiencies in the standard preclinical methods for evaluating potential anticancer drugs,such as xenograft mouse models, have been highlighted as a key obstacle in the translation of the major advances in basic cancer research into meaningful clinical benefits. In this article, we discuss the established uses and limitations of xenograft mouse models for cancer drug development, and then describe the opportunities and challenges in the application of novel genetically engineered mouse models that more faithfully mimic the genetic and biological evolution of human cancers. Greater use of such models in target validation, assessment of tumour response, investigation of pharmacodynamic markers of drug action, modelling resistance and understanding toxicity has the potential to markedly improve the success of cancer drug development.

Dissecting eIF4E action in tumorigenesis

Abstract: Genetically engineered mouse models are powerful tools for studying cancer genes and validating targets for cancer therapy. We previously used a mouse lymphoma model to demonstrate that the translation initiation factor eIF4E is a potent oncogene in vivo. Using the same model, we now show that the oncogenic activity of eIF4E correlates with its ability to activate translation and become phosphorylated on Ser 209. Furthermore, constitutively activated MNK1, an eIF4E Ser 209 kinase, promotes tumorigenesis in a manner similar to eIF4E, and a dominant-negative MNK mutant inhibits the in vivo proliferation of tumor cells driven by mutations that deregulate translation. Phosphorylated eIF4E promotes tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 is one target of both phospho-eIF4E and MNK1 that contributes to tumor formation. Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention.

Non-Transgenic Mouse Models of Kidney Disease

Abstract: Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches. Recently, interventional models suitable to induce acute and chronic kidney disease in the mouse have become a focus of interest due to the wide availability of genetically engineered mouse lines. These models differ by their damaging mechanism (cell toxicity, immune mechanisms, surgical renal mass reduction, ischemia, hypertension, ureter obstruction etc.), functional and histomorphological phenotype and disease evolution. The susceptibility to a damaging mechanism often depends on strain and gender. The C57BL/6 strain, the most commonly used genetic background of transgenic mice, appears to be relatively resistant against developing glomerulosclerosis, proteinuria and hypertension. This review serves to provide a comprehensive overview of interventional mouse models of acute and chronic kidney disease.