Tumor genotyping: waiting for a breakthrough

Cancer mutation as the main hope
A recent report on the success of a new drug to combat melanoma tells us that we live in an era when the main question tormenting a cancer patient is: "What mutation do I have?"Irina Yakutenko, Snob magazine
The other day, an article appeared in The New York Times newspaper that a group of American doctors at the Abramson Cancer Center at the University of Pennsylvania — one of the leading clinical centers in the United States where cancer research and treatment is carried out — tested a new drug for the treatment of melanoma, and the results of the first clinical trials were extremely successful (After Long Fight, Drug Gives Sudden Reprieve).

However, the very next day a new article about the same drug (A Drug Trial Cycle: Recovery, Relapse, Reinvention) appeared in the newspaper, and its tone was by no means so joyful. Moreover, it was reported that some of the patients who were initially helped by the new drug died, and died of melanoma. It seems that the readers of this respected publication were surprised by such an unexpected change of tone. Let's try to figure out what kind of drug it is and whether there has been a revolution in cancer treatment methods.

First, let's disappoint readers: there was no revolution. The new drug, as it turned out, is able to kill cancer cells, but is not able to completely cure patients from a terrible ailment. The importance of this drug is that it allows people to buy time — time when they can lead a relatively comfortable life and not experience pain. But, alas, not all patients will be able to buy time, but only those of them whose cells carry a certain specific mutation. And this is a fundamental moment that determines the development of modern cancer treatment methods: the drug under study is one of the numerous compounds that treat cancer in a targeted manner today. That is, they do not just kill any dividing cells, but affect strictly defined processes in cells with strictly defined mutations.

In general, in recent years, the approach to the perception and treatment of cancer has changed dramatically. Now a person, having learned that he has cancer, first of all asks the question: what kind of mutation do I have? And this can already be called a revolution.

Melanoma is one of the most common types of cancer on Earth and one of the most dangerous. Melanoma accounts for about 3 percent of all skin cancers, but it is responsible for 75 percent of deaths from this type of cancer. And what is most unpleasant, for many patients with melanoma, standard methods of therapy — radiation and chemotherapy — do not give results. That is why doctors are actively developing methods of targeted therapy of melanoma.

The drug used by the heroes of The New York Times publication is indigestibly called PLX4032. It only works in cancer cells carrying the V600E mutation in the BRAF gene. PLX4032 blocks the operation of BRAF, which, in turn, leads to the shutdown of the RAF-MEK-ERK signal circuit... Stop, stop, stop. All these abbreviations, it seems, do not allow us to understand at all how the new drug works. Let's go from the other side.

Imagine that you have a special microscope with which you can see what is happening inside living cells. Moreover, you are not observing a hodgepodge of moving structures, but only those reactions and processes that are critical for the survival of the cell.

Your objects of observation are two melanoma cells that look almost identical to each other. The only difference: in the genome of the first cell in one of the genes (BRAF) there is a violation, a mutation that scientists call V600E. There is no such mutation in the genome of the second cell — in this it is similar to all other cells of the patient's body. We increase the sharpness of our microscope and see that reactions take place in both cells involving three proteins — RAF, MEK and ERK. As we remember, our microscope shows only the processes most necessary for cell life. So, if you block the chain of RAF-MEK-ERK reactions, both cancer cells will die. To stop the reactions, you can "turn off" one or more of the three proteins. For example, the first protein in the chain, RAF, can be taken out of the game.

To do this, we will need a new medicine — PLX4032. It just blocks the work of the RAF protein. We add the drug to our cells and look at the result. In the second cell — which does not have the V600E mutation — we still see all the reactions. The fact is that the normal, non-mutant BRAF protein turns on an alternative mechanism in cells that compensates for the "shutdown" of RAF. In the first cell in which the BRAF protein is damaged by a mutation, an alternative mechanism cannot be activated. Therefore, a critical chain of reactions breaks down, and the cell dies.

After many preparatory studies, doctors recruited a group of volunteers with melanoma whose cancer cells carried the V600E mutation, determined the optimal dose of the drug (that is, such a dose when the therapeutic effect is maximally pronounced with minimal side effects) and began a course of treatment.

In the first few months, the development of melanoma slowed down in almost all patients, the tumors began to shrink in size and even disappear. Most of all, doctors were struck by the effect of the drug on a patient whose body was literally clogged with tumors: after 15 days, most of the neoplasms disappeared.

Before the start of the tests, doctors gave him no more than a month. It seemed to be an absolute triumph. However, a few more months passed, and the patients began to get worse. Despite the constant intake of PLX4032, tumors began to spread through their bodies again. On average, melanoma prevailed over the drug nine months after the start of the course of treatment. Two patients have already died.

Doctors believe that the disease is returning for the reason that cancer cells find a workaround and manage to launch the ill-fated chain of RAF-MEK-ERK reactions. For example, a mutant BRAF can activate some other protein that takes over the duties of a "disabled" RAF. In order to test this hypothesis, it is necessary to find out what kind of protein it is, select an inhibitor for it and conduct clinical trials in which patients will take both this inhibitor and PLX4032. Selecting an inhibitor and testing it together with PLX4032 will require a lot of time and financial costs, so pharmaceutical companies are not eager to start all these procedures immediately; I must say, there is another business conflict that I can tell you more about in the comments.

If pharmaceutical companies do give the go-ahead, then any patient with the "right" mutation will be able to take part in the trials. According to statistics, about 60 percent of patients with melanoma carry the V600E mutation. You can check for the presence of a mutation in any hospital in the United States (and in some medical institutions in Russia).

So, PLX4032 could not completely rid patients of melanoma. However, thanks to him, the patients were relieved of pain for at least nine months and spent an extra nine months with their loved ones. As the wife of the very patient who started participating in the trials said, having at best a month left (PLX4032 allowed him to last another year): "It was a year that I wouldn't trade for anything." I think this result is worthy of research.

There are many drugs like PLX4032 that treat certain types of cancer, targeting certain mutations, and their number is constantly growing. With their help, doctors fight, for example, breast cancer, non-small cell lung cancer, various types of lymphomas and myelomas. Not all of them are equally effective. But the more doctors and scientists investigate the effect of such drugs, the clearer one point becomes: the success in using a particular drug directly depends on how specific it is.

For cancer patients, the results of genetic analysis become perhaps the most important results in their lives. Is there a mutation or not? If there is — will the drug work or will it not work?

Yes, cancer cells have learned to bypass these specific drugs — they mutate and begin to multiply, despite taking the medication. But, nevertheless, this is already a counterattack, not a massive offensive.