Having a mutated TP53 gene wouldn’t be such an issue if there was a way of fixing the mutant p53 proteins that the gene produces. It’s not such a crazy idea – there are already some experimental drugs being produced which can do some of that. Galina Selivanova and her colleagues have worked on the drugs RITA, PRIMA-1 and PRIMA-1-Met (APR-246), as we discussed on our site here. Currently there are a number of clinical trials of APR-246 in different cancers – where the drug works by reactivating the mutant p53 proteins produced in cancer cells so that they work like non-mutated p53 proteins.
However, a recent paper has shown some seriously impressive results in reshaping mutant p53 using an existing drug rather than a newly developed one. What’s more, the drug seems to be working on p53 mutations which are common in LFS. The drug is Arsenic Trioxide (ATO), a drug already used clinically in the treatment of acute promyelocytic leukemia. What has not been known to date is that the drug can also reshape mutant p53 proteins so that they function like non-mutated proteins and can knock out cancer cells.
Using mice carrying tumours with different TP53 mutations the authors of the paper showed that treatment with ATO reduced tumour growth. What’s more they also showed that using ATO with the chemotherapy drug cisplatin had even better results as the two drugs worked together. ATO didn’t work as well on all types of TP53 mutations, but for the majority the results were positive. Of course testing in mice is one thing, testing in humans is what really counts. To this end the authors are carrying out a trial using ATO and the chemotherapy drug decitabine in patients with p53 mutant high-risk AML/MDS patients in China.
While the TP53 mutations used in the paper are also found in LFS, the mutations were what is called ‘somatic mutations’ – that is they were only in the cancer cells, not all the cells as in LFS. However, in a piece of really positive news, Min Lu, one of the lead authors of this research, has confirmed that they are also working in mouse models of LFS. The data is not published yet but it is looking extremely interesting for people with LFS. Even more interesting is that the same group are now working on another drug that works in the same way but which doesn’t have the toxicity associated with ATO. This is really exciting news – watch this space!