Eh, guys, it's not like that…

Most cancer drugs are rejected when tested

Julia Belluz, Vox: Most cancer drugs fail in testing. This might be a big reason why. Translated by Alexander Gorlov, XX2 century

For links, see the original article or translated – VM.

The statistics of failures are staggering: in 97 percent of cases, a new drug designed to fight a particular form of cancer does not enter the market after clinical trials. Consequently, people (and animals) who are attracted to these trials risk their lives for the sake of unsuccessful treatments.

And now a study has been conducted to help understand why the percentage of failures is so high: in the case of targeted cancer therapy – a relatively new class of cancer treatment – drugs may not achieve the goals set by researchers.

Targeted cancer treatments work differently than traditional ones, such as chemotherapy. The drugs used in these new methods, according to their creators, target specific genes, proteins or tissues that favor the growth of cancer cells. (On the other hand, for chemotherapy, which usually acts on all cells without exception, which are rapidly dividing, it does not matter which of them are cancerous and which are healthy).

The results of the aforementioned new study are published in the journal Science Translational Medicine. The authors of this work used CRISPR–the newest and most accurate gene editing tool available–to test whether 10 different drugs work the way they should. In all cases, it turned out that they did not work.

When the authors of the article removed the genes from the genomes of cancer cells, without which, as it was believed, the growth of a cancerous tumor was impossible, the tumor continued to grow. And when they used drugs aimed at genes removed from the genomes, each one at one gene out of six, the absence of target genes did not prevent these drugs from killing cancer cells at all. In other words, the drugs worked even after removing the target they were supposed to hit.

Apparently, these facts should be interpreted as follows: the main reason for the failures of cancer drugs in their clinical trial is that these drugs actually do not work as they should work, according to the calculations of their creators.

"I hope that this scientific work will help to realize the need to improve the selection and justification of targets for targeted cancer drugs," said William George Kaelin, professor of medicine at Harvard University, who was not involved in this study.

In addition, the results of this work should be a wake-up call for drug developers. "It should be checked whether their drugs work after the removal of the target protein," says Nathanael Gray, a biologist and oncologist at the Dana–Farber Cancer Institute, who also did not participate in the study.

The discoveries made by the authors of the article are certainly impressive. But no less impressive is the story of what prompted these scientists to immediately take up this study and use the latest gene editing technologies to re-analyze and possibly refute previous clinical research results.

The breast cancer drug that initiated the investigation of why targeted drugs are rejected during testing

A few years ago, one of the authors of the article, Jason Sheltzer, a researcher at the Cold Spring Harbor Laboratory studying cancer biology, and his colleagues became interested in the MELK gene, which is considered a good biomarker for aggressive breast cancer in patients with a poor prognosis. In 2019, approximately 201,000 cases of invasive breast cancer will be diagnosed in the United States, and, according to According to the American Cancer Society, about 42,000 women may die from this disease.

Schelzer and his colleagues, having taken up the study of this gene using CRISPR, found that they could not reproduce many of the results of earlier work on MELK, where gene analysis was carried out using old technologies, in particular RNA interference. The main discovery was this: breast cancer cells continued to divide even after the removal of MELK.

When clinical trials of a targeted drug that was supposed to affect MELK in breast cancer began, the researchers re-applied CRISPR. This time, using this tool, they cut out the MELK to see if the drug being tested would work. The removal of the target gene, which was targeted by the drug, did not affect its work in any way. "We found that this drug continued to kill breast cancer cells," said Schelzer.

This discovery, the scientist recalls, made him and his colleagues think seriously. What result did they get: did they just identify "an incredibly hacky cure for cancer or stumbled upon a more serious problem"? "The extremely high percentage of failures [in clinical trials of cancer drugs] caused us to suspect that cases of testing poorly developed drugs on humans with poorly studied hitting the intended target are far from isolated."

There should be more oncological studies on reproducibility of results

Consider a new study. Schelzer and his co-authors selected 10 targeted drugs, which, as in the case of MELK, were at different stages of clinical development. The researchers focused mainly on targets detected by RNA interference, a once-popular gene analysis technology, a precursor to CRISPR. It was necessary to find out whether the developers of the drugs, as in the case of MELK, were on a slippery slope.

In all the experiments, Schelzer and his colleagues observed the genomes of cancer cells. From these genomes, they used CRISPR to cut out genes, allegedly (so it was thought) significantly affecting the growth of a cancerous tumor. And here's the result: all the drugs continued to kill cancer cells after removing the target genes that these drugs were supposed to affect.

"The 10 drugs we studied turned out to be strong anti-cancer drugs. Therefore, we believe that if we can figure out how these drugs actually work, we will be able to identify new target genes or find the most suitable patients," says Schelzer.

In addition, it is possible that the false targeting discovered during the study will help to understand why drugs are not being approved, going through increasingly stringent stages of clinical trials.

However, failures to hit targets can be explained in another way. Schelzer admits that he and his colleagues chose drugs created using RNA interference technology. And "technology is always improving. Therefore, many drugs that are currently being tested on patients were created and characterized five to ten years ago." It is possible that thanks to the use of new genetic technologies, targeted therapies developed in recent years are much more accurate.

Kaelin and Gray urged not to rush to evaluate the study conducted by Schelzer and his colleagues, because these researchers undertook to study targeted drugs that were already considered problematic. According to Kaelin, "[they] selected for analysis such drugs whose ability to accurately hit targets, in my opinion, did not have a solid genetic justification." Therefore, it can be expected that cancer drugs that are more carefully targeted at certain targets will work exactly according to their intended goals.

However, according to Schelzer, the research plan provided for the analysis of exactly bad developments. "A lot of anti–cancer drugs go into clinical trials with extremely weak genetic justification, and it is worth looking at them - as it immediately becomes clear that they are not able to accurately hit certain target genes."

Anyway, Schelzer and his colleagues hope that their study will serve as an impetus for further analysis of the ineffectiveness of many cancer drugs. "The agencies that finance cancer research are extremely interested in developing more and more new drugs," says Schelzer, "and they are not enthusiastic about our research on the problem of reproducibility and inefficiency of some drugs." And it will not hurt these financiers to address this problem, since we want to accelerate the development of new effective cancer treatments.

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