Breeding of a human AXL knock in mouse

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Development of drug resistance is a major obstacle in treatment of cancer. Lately, the important role of epithelial to mesenchymal transition (EMT) in development of resistance both towards targeted therapy and conventional chemotherapy has become evident. The role of EMT also in other disease mechanisms such as fibrosis development is also becoming evident. BerGenBio develops drugs specifically targeting kinases that are important drivers in the EMT process.

Although EMT is essential for numerous normal developmental processes and wound healing, EMT has been shown to play an important role in initiation of cancer, development of metastasis for cancer progression, therapy resistance and over activation of the scarring process evident in fibrosis. A growing body of evidence shows that acquisition of EMT by cancer cells accounts for resistance mechanisms to current chemo- and immuno-therapeutics across various types of cancers. EMT is therefore an attractive target for cancer therapy. Numerous publications have reported increased activation of Axl and EMT in association with acquired resistance to targeted therapy and chemotherapy. BerGenBio have proven in several mouse model of breast, prostate and lung cancer that inhibition of enzymes and receptors that mediates the EMT phenotype enhances sensitivity to standard chemotherapeutics and targeted therapy, and even more important, reverse or prevent development of drug resistance. BerGenBio has also proven in models of fibrosis that inhibition of the EMT phenotype prevents a fibrotic phenotype. BerGenBio has developed small molecule inhibitors against AXL already in Clinical Trials. We are now developing humanized antibodies against AXL for translation into man.

In order to investigate the effect of humanized AXL antibodies in murine models we have generated a human AXL knock in mouse (huAXL-KI). The colony will start with 5-10 breeding pairs and will be extended/maintained from these. The described project will set up a breeding colony of the huAXL-KI mouse for subsequent utilization of this mouse model in exploratory syngeneic models of cancer and other indications where EMT has proven to be an important mechanism of disease progression such as fibrosis. The mice obtained in this breeding will be utilized in approved FOTS applications where C57Bl6 mice are being used to investigate the potential therapeutic use of AXL inhibition in cancer and fibrosis. The breeding protocol does not inflict severe distress to the mice. We are applying for a total of 750 mice for this project.

Replacement, Reduction and Refinement
An extensive amount of in vitro and in vivo studies have already been performed to validate AXL as a drug target in several models of cancer and fibrosis. As cell culture studies can not replace the complexity of a mouse model in response to drug treatment, in vitro results needs validation in mouse models as pre-clinical proof of concept. Specific Replacement, Reduction and Refinement precautions issued for selected down-stream experiments will be described in detail in the accompanied FOTS applications.
The mouse strain will be bred with homozygous breeding pairs so no unwanted genetic backgrounds are obtained. Both females and males can be used for exploratory therapeutic models.