Forsøksdyr: Inhibition of FGFR4 activity and downstream signaling effectors in a mouse model of Rhabdomyosarcoma

Godkjenningsdato 27.01.2020

Godkjenningsperiode 01.02.2020-31.01.2024

Point mutations in FGFRs have been uncovered in a number of cancers. One important example is the childhood cancer Rhabdomyosarcoma, which is often caused by point mutations in the kinase domain of FGFR4 (for instance V550L mutations).We have through our basic research found that cells with FGFR4 V550L mutation get oncogene-addicted to this signal. Thus, the cells do not proliferate when the activity of FGFR4 is inhibited by drugs like LY2874455 or FGF410/H3B-6527, or by siRNA knockdown of FGFR4. We now need to validate these findings in an animal model and want to test the anti-tumor activity of FGFR4 inhibitors in a mouse xenograft model.

The experiments performed in this application involve procedures where the animals are given a one time injection of cells, followed by oral treatments with one of the inhibitors LY2874455 or FGF410/H3B-6527 two times per day for up to four weeks. In our experience oral administartion of drugs two times per day is well tolerated, with few/no signs of throat injuries, minimum weight loss and normal open field behaviour. The toxicity that might occure is related to the drug that is given. To the best of our ability we will stribe to keep the treatment doses of the inhibitors in a range that will minimalize the weight reduction/toxicity in the animals. However, some of the animals might be negatively affected so that the severity of the experiments will be classified as moderatley influencing animal well-fare.

Since children with metastatic rhabdomysracoma are in need of improved treatment options, the therapeutic potential of LY2874455 and FGF410/H3B-6527 should be more carefully assessed using rhabdomysracoma xenograft models.

We apply for the use of 206 nude mice over a period of four years.

I) In vitro experiments using cell cultures can sometimes be an alternative in testing cancer treatment strategies, however they are often limited as a screening method for evaluating the treatment efficacy in pharmacological relevant doses. However, to generate treatment data to support clinical testing, animal studies must be performed.

II) We have conducted statistical power analyses to determine the minimum required sample sizes to obtain significant results.

III) Appropriate experimental endpoints that allow for early intervention have been implemented to reduce animal suffering. Handling of the animals will be performed by experienced personnel so that the discomfort/stress to the mice will be at a minimum. We have experience delivering drugs oraly two times per day without any noticable negative effects on the mice. The environment of the mice will be enriched with soft paper and plastic houses.