Forsøksdyr: Inhibition of Axl to improve therapies for drug resistant cancers

Godkjenningsdato 08.12.2020

Godkjenningsperiode 08.12.2020-07.12.2024

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.
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 through interaction with the Cancer Stem Cell (CSC) gene program, development of metastasis for cancer progression and therapy resistance. A growing body of evidence shows that acquisition of stem cell-features by cancer cells accounts for resistance mechanisms to a wide variety of current chemo- and immuno-therapeutics across various types of cancers. EMT is therefore an attractive target for cancer therapy.

We hypothesize that inhibition of enzymes and receptors that attenuate the EMT-cancer stem cell phenotype will enhance sensitivity to standard chemotherapeutics and targeted therapy, and even more important, reverse or prevent development of drug resistance. Our discovery of the role of the Axl tyrosine kinase in maintaining EMT in breast cancer provides experimental support for this hypothesis. Numerous publications have reported increased activation of Axl and EMT in association with acquired resistance to targeted therapy and chemotherapy.

Our company has developed small molecule inhibitors and targeting antibodies against AXL. In support of our pre-clinical program to take these inhibitors into the clinic, the aim of these studies is to investigate strategies for combination treatment regimes to enhance therapies for drug resistant cancers. We are applying for the use of a maximum of 720 NUDE mice, 120 NODSCID and 120 NSG mice to be able to investigate the efficacy of EMT inhibitors in combination with targeted therapy and chemotherapy in multiple indications including cancers of the skin, ovary, blood, breast, lung, pancreas and kidney. The expected accumulated harm to the animals will be classified as moderate based on animal models, duration, nature of effects and interval of procedures.

Replacement, Reduction and Refinement
An extensive amount of in vitro studies have been performed to validate our drug targets and select indications where EMT is an important resistance development mechanism and where EMT inhibition therefore can mediate re-sensitisation to standard of care therapy to identify the indications and cell lines that needs validation in mouse models. As cell culture studies can not replace the complexity of a mouse model in response to drug treatment, in vitro results need validation in mouse models as pre-clinical proof of concept.
For subcutaneous xenograft models, two tumors will be utilized per mouse. For tumor growth analysis, measurements of the same animals will be used across the time. For some experiments non-invasive imaging techniques will be used. The personnel performing the procedures of animal handling, cell injection and subsequent administration of drugs to the animals and that are responsible for the wellbeing of the mice are well trained and experienced in these methods.