Reviving the Guardian of the Genome – A New Method for Reactivating p53 Mutants for Cancer Therapy

What is it about?

The tumor suppressor p53 is the most mutated gene in cancer and has been the target of many drug developent projects but has turned out to be very difficult to reactivate. Now a research consortium comprising research groups from the universities of Frankfurt, Marburg, Cologne, and Zurich has described a new, groundbreaking method in a study recently published in the journal Proceedings of the National Academy of Sciences (PNAS) that can reactivate a wide variety of p53 mutants. This method is not based on the synthesis of small molecules, but on the development of Designed Ankyrin Repeat Proteins (DARPins) that bind to p53 very selectively and with high affinity. The consortium was able to demonstrate that, through the binding of such a DARPin, a large number of p53 mutants regain sufficient stability, thereby reactivating the tumor-suppressor function of p53 in cancer cells. The major advantage of this approach is that this DARPin stabilizes not just a specific p53 mutant, but many different ones, which could benefit an estimated 2.5 million new cancer patients annually in the future. This also means that a specific drug does not need to be developed for every mutant.

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Why is it important?

Every year, 20 million new cases of cancer are diagnosed worldwide. In about 50% of these cases, the key tumor suppressor protein p53—also known as the “guardian of the genome”—is inactivated by a mutation. This makes p53 the most frequently mutated gene in tumors. In many cases, the mutation causes p53 to become unstable and lose its functional structure. Due to its central importance, researchers have been searching for decades for therapeutic approaches to stabilize such p53 mutants and thereby reactivate them—in the hope that this will cause cancer cells to die in a targeted manner. An initial clinical success with this approach was recently reported by the company PMV Pharmaceuticals. The small molecule rezatapopt can reactivate a specific mutation in p53 and thereby inhibit the growth of tumors with precisely this mutation. However, more than 2,000 different mutations have already been described in tumors. Only a very small fraction of these creates a binding pocket suitable for the development of classic, small-molecule-based drugs. The DARPin described in the PNAS publication can reactivate virtually all so-called temperature sensitive p53 mutants that includes up to one-third of all p53 mutants across various cancer types.

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