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!
Joanna Zawacka-Pankau
Thank you for the post, Pan. Indeed, interesting work. Yet, it is excellent that you have mentioned PRIMA-1Met and APR-246. What I find especially valuable about this publication is that ATO induces an allosteric shift in p53 by binding to cysteine residues, including Cys 124 in p53 DNA binding domain. With Klas Wiman, who with colleagues, discovered PRIMA-1, we have shown that APR-246 (Eprenetapopt) binds to Cys124 and Cys277 to reactivate mutant p53 (LFS Conference 2018 UK). Arsenic trioxide might indeed be too toxic, thus it would be of relevance to see how APR-246 would work in LFS pre-clinical models.
Pan
It would be really great to see more work on APR-246 in LFS – any chance you can suggest that to some of your colleagues?
Joanna Zawacka-Pankau
Yes, I agree. I am aware that Klas Wiman’s group is working on it. Hopefully, more information will come soon.
Lorraine
Could arsenic trioxide or apr 246 be used on people who have a tp53 mutation but no cancer , YET !!
Pan
That’s the ultimate aim – to find drugs that reduce the risk of getting cancer in people with a TP53 mutation who’ve never had and never will have cancer. But a drug that can do that has got to be really safe and have few side effects. After all, you don’t want to be taking stuff every day that’s going to make you ill. That’s why we’re looking at drugs like metformin and aspirin first.
Jerry
A scientist from a p53 lab told me that Dr. Lu’s paper was really really really impressive. His lab tested and found clinical-established old drug arsenic could convert mutant p53 into wild-type p53 with at least 100-time efficiency than any of the existing mutant p53-targeted compounds reported in the past decades. He also said in the Cancer Cell paper it is for the first time scientists see how a drug can convert various p53 mutants into wild-type p53. Its really exciting.
Lorraine Silberberg
What if it is a splice mutation, with a partial protein, or no protein at all , I m not a scientist but I presume it can’t work ?
Min Lu
Both atom-level mechanism and experimental data clearly show ATO can not rescue a splice mutations, DNA-contacting mutations, or truncating mutation.
Both atom-level mechanism and experimental data clearly show ATO can only rescues strcutural mutations and these structural mutations trends to have one of these features: large-to-small amino acid substitution, near the arsenic-binding pocket, temperature-sensitive, occurring on hydrophobic residues, occurring on the LSH motif (based on this paper https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjab007/6122705).
For some pre-mature-stop-code truncation p53 mutations, there is some antibiotics such as G418 that can convert this mutant p53 into ‘wild-type’ p53 in laboratory. I am not sure whether these antibiotics enters clinicals.
Lorraine Silberberg
Thank you for taking the time to answer
I really appreciate it