p53: Who’s Arousing The Tumour Slayer?

27. December 2016
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p53 is one of the body's most important weapons against cancer. In most tumours the tumour suppressor gene is however mutated. Scientists have for a long time been trying to retrieve this "guardian of the genome". The pharmaceutical giants are now enthusiastically getting in the mix.

Not many molecules make it onto a title page. In 1993 p53 graced the cover of the prestigious specialist journal Science. The protein can prevent the development of cancer. If damage in the genetic tissue appears, p53 halts the cell cycle and induces molecular mechanisms for repair. If the defect is too severe, p53 sends the cell to the cellular retirement home or straight to its death. Its skills earned it the title “guardian of the genome”. The protein has since become something like a pop star among molecular handymen in our body.

Why does cancer despite that still rank among the most common causes of death? Because p53 can be switched off. In many tumours, the gene for p53 (TP53) has already been altered. Many mutations cause the shape of the subsequently formed protein to be changed and to therefore no longer work. In other cancer cells molecules are active that make the protein incapable of action. MDM2 is such a molecule. It binds to p53 and ensures that p53 gets degraded.

New hope for reviving the guardian

Retrieving the guardian protein rates among the biggest dreams of cancer researchers. Hardly any other protein has been studied as closely in recent decades. Yet despite all efforts, no drug seems to have made it to the market. This may now be changing. Many scientists are currently trying to strengthen p53 wherever it still remains intact. If they prevent molecules such as MDM2 from withdrawing too much of the tumour suppressor from the body flow, enough of the protein still remains in the cell to eliminate the tumour cells.

The fact that the approach works is something known from animal and cell studies. After many setbacks, the first clinical trials are now underway. The pharmaceutical giants Merck, Amgen, Novartis and Sanofi-Aventis have developed inhibitors for testing for the first time on patients with solid tumours, blood cancer or multiple myelomas. Roche is now investigating its own idasanutlin in a phase III trial. The company is investigating the use of inhibitors against AML (acute myelogenous leukemia). Early clinical studies involving the inhibitor also exist for prostate cancer, multiple myeloma and lymphomas.

And with neuroblastoma as well scientists hope to have success with this approach. The malignant tumours of the nervous system are among the most common fatal cancers in children. Despite therapy it’s still the case that fewer than half of them survive.

Little has been previously known about possible side effects of inhibitors. As scientists in 2012 tested a blocker of tumours of the fat tissue, the number of certain immune cells (neutrophils granulocytes) in some patients dropped dangerously. Should the new active agents meet the researchers’ expectations, they will probably be the first p53 drugs on the market.

Heal p53 when it’s sick

But what about with types of cancers where there isn’t enough intact p53? If p53 is mutated, this approach no longer helps. Therefore, a handful of laboratories and research groups have a second strategy: heal p53 when it is sick. It is the more difficult path, but it might be worth the effort. This is because a p53 protein altered by mutation loses not only its ability to send defective cells to commit suicide. The altered protein can also become an oncogene, making it a cancer growth driver which promotes the invasion of cancer cells, drives metastasis or unchecked proliferation.

The solution would be to return p53 to its old form, to find a lever which makes the alteration reversible. Researchers led by Rommie Amaro several years ago set out on this search and with the help of supercomputers imitated a dynamic model of p53.

Possible stabilisation through molecules

In the simulations they found a small sac in the heart of the protein. “In the normal p53 protein it only opens for a very short time”, says Peter Kaiser, a professor of biological chemistry at the University of California. In p53 mutants, however, which are found in tumours, they stay open much longer. Molecules that bind in the gap during this time can rebuild the function of p53.

From looking at one active agent we now know that it attaches right there. APR 264 stabilises the protein just enough so that it can work again. In 2012 this active agent made it through the first round of safety studies on the drug. It was studied in patients with blood cancer. In a phase II study renowned scientists tested the therapy precisely on women with ovarian cancer. There, too, mutated p53 almost always plays a role.

Sticking a mutation in the sac

In their search for new drugs, the group led by Kaiser and Amaro have now studied more than two million substances using their computer models. Nearly 3,000 candidates have been found which could fit into this sac. The researcher believes that about ten to 15 percent of these molecules could reactivate mutated p53 proteins in tumour cells. The substances need to stabilise p53 to the extent that it might work again. Thus, the mutated cells would be killed, “but not those with normal p53”, says Kaiser. In order to further investigate some promising active agents, the scientists have founded a biotech firm.

This achievement could pay off. That’s because some of these molecules appear to work with almost all p53 mutations. With just a few active substances, one might be able to make advances against p53 mutations in the greatest variety of tumours. If the stabilisation idea works out, even patients who are not suffering from cancer might one day benefit. Because with other diseases as well it is deformed proteins that cause the problem. Alzheimer’s is just one of these.

First however, all these agents have to demonstrate not only their efficacy but also their safety in many further studies. One does not as yet know what the consequences are when re-establishing the functioning of a damaged version of the body’s own mechanisms. Whether the dream of cancer researchers will be realised will therefore only be found out in a few years.

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