Forsøksdyr: Targeting the AHR-TIPARP axis to reduce tumor growth

Godkjenningsdato 17.12.2020

Godkjenningsperiode 01.02.2021-31.01.2025

1 Purpose
The immune system plays dual roles in cancer. It can suppress tumor growth by destroying cancer cells but it can also promote tumor progression by selecting for cancer cells that survive in an immunosuppressive environment to facilitate tumor growth. Signaling molecules, called interferons, activate immune cells in such a way that they destroy cancer cells. Targeting immune cells in cancer, known as cancer immunotherapy, has led to some exciting and long-lasting responses in patients, but improvements are necessary so that more patients can benefit from this treatment. The protein TIPARP also known as PARP7, together with the protein AHR block the activation of interferons and thus allow tumors to proliferate. Inhibiting or deleting TIPARP or AHR are new potential treatment strategies for many difficult to treat cancers. In this project we will test the ability of inhibition of TIPARP and/or AHR to suppress or prevent tumor growth in wildtype and genetically modified mouse models, where TIPARP or AHR genes have been deleted.

2 Distress
Mice will receive transplanted human or mouse cancer cells, in some experiments small molecule inhibitors will be administered. Tumor growth will be monitored. The mice will undergo moderate distress, but they will be humanely euthanized when the reach humane endpoints based a score sheet and tumor size to avoid any unnecessary stress.

3 Expected benefit
Our results will potentially lead to new therapeutic strategies to treat cancer and improve survival and quality of live for many patients. We will test both male and female mice to address potential sex-dependent effects. Results from our work may lead to rethinking of exist therapeutic strategies for cancer treatment.

4 Number of animals, and what kind
We will require three thousand seven hundred and sixty two mice which includes experimental animals and those used for breeding and maintenance of the different genetically modified colonies.

5 How to adhere to 3R
Non-animal alternatives do not exit that accurately model pharmacodynamic and pharmacokinetic differences and immune cells responses that occur in intact animals, preventing complete replacement. However, we will isolate primary immune cells from the mice that will be used in lab-based studies to reduce the number of animals needed for our studies. We will also strictly adhere to our established protocols and score sheet to minimize stress pain and discomfort to the mice.