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In search of the next cure for cancer, few researchers are bothered to take a look at the cemetery of failed drugs to understand what went wrong.
The number of failures is staggering: a new drug is tested as part of a clinical trial for a particular type of cancer in 97% of cases it is never put on the market. This means that humans (and animals) who participate in these experiments risk their lives during treatments that end up in the trash.
A new study now helps explain why the failure rate is so high: In the case of targeted cancer treatments – a relatively new class of oncology drugs – the drugs may not achieve the goals sought by researchers.
Targeted cancer therapies work differently than traditional therapies, such as chemotherapy. They are supposed to target genes, proteins or specific tissues on which cancer cells melt to grow. (Chemotherapy, on the other hand, usually works on all cells that divide rapidly, whether healthy or cancerous.)
The new study, published in Translational medicine science, used CRISPR – the latest and most accurate gene editing tool available – to examine whether 10 different drugs were working as intended by the researchers. In all cases, the researchers found that they had not done so.
When the authors of the document removed genes from the genomes of cancer cells that were thought to be essential for cancer growth, the cells continued to grow. And when they applied the drugs – each targeting one of the six genes – to the newly deleted genes, the drugs still killed the cancer cells. In other words, even when the supposed target of the therapies was completely removed, the drugs worked.
This suggests that it is possible that one of the main factors of failure of anticancer drugs in clinical studies is that the drugs do not really work as expected.
"I hope this paper will help people understand the need to define and validate cancer drug targets," said William George Kaelin, professor of medicine at Harvard University, who said he would not be able to help. did not participate in the study.
The study should also be a warning for drug developers: "[They] have to make sure their drugs stop working if the target protein has been genetically deleted, "said Nathanael Gray, a cancer biologist at the Dana-Farber Cancer Institute, who was also independent of the research.
The discovery is really fascinating. But that's also the story of why researchers decided to start the study and use the latest gene-modification technology to reanalyze or even reverse previous discoveries of cancer clinical studies.
A breast cancer drug that paved the way for the study of targeted drug failure
A few years ago, one of the authors of the paper – Jason Sheltzer, a researcher in cancer biology at Cold Spring Harbor Lab – and his colleagues were interested in a gene called MELK, believed to be a biomarker for breast cancer. aggressive breast patients with poor prognosis. In the United States, some 270,000 new cases of invasive breast cancer will be diagnosed in 2019 and nearly 42,000 women are at risk of dying from this disease, according to the American Cancer Society.
Researchers began tinkering with the CRISPR gene and found that they could not replicate many of the previous discoveries on MELK that had been discovered using older gene analysis technologies, such as RNA interference. Namely, even when MELK was cut, breast cancer cells proliferated.
When a drug purporting to target MELK for breast cancer entered clinical studies, the researchers decided to use CRISPR again, this time to modify the gene to see if the drug was still working. "We found that the drug continued to kill breast cancer cells," whether the target MELK is present in the breast cancer genome or not, Sheltzer said.
This led Sheltzer and his colleagues to ask themselves a big question: did they just study "a particularly bad anti-cancer drug or did we come across a bigger problem?", He recalled. "The extremely high failure rate [in cancer clinical trials] made us suspect that there could be other cases of poorly designed drugs and poorly studied drug targets being tested in human patients. "
We need more research on reproducibility in anticancer medicine
Enter the new study. Sheltzer and his co-authors chose 10 drugs and drug targets that, like MELK, were at different stages of clinical development. They focused primarily on targets discovered through RNA interference, again, a very popular gene analysis technology that preceded CRISPR. And they suspected that – like MELK – it might have led researchers to the wrong path.
In each case, they used CRISPR to cut genes into the genomes of the cancer cells they were examining – genes considered essential for cancer growth. And they discovered that in all cases, the drugs killed the cancer cells even though the gene believed to lead to cancer had been removed.
"We ended up with 10 drugs that are potent anticancer agents. So we think that if we can find out what these drugs are doing, we may be able to discover new cancer targets or more likely patients to respond, "said Sheltzer.
It is also possible that this type of erroneous target helps explain why drugs do not meet expectations as they go through increasingly rigorous steps in clinical trials.
But there could also be other explanations for missed targets. Sheltzer acknowledged having chosen drugs primarily discovered with RNA interference technology. And, "Technology is constantly improving. Thus, many of the drugs currently tested in patients have been discovered and characterized five to ten years ago. It is possible that targeted therapies, discovered more recently using newer genetic technologies, may be more accurate.
Kaelin and Gray both cautioned against this study: the researchers focused on targeted drugs that were already known to be problematic. As Kaelin said:[They] I chose drugs for targets for which there never existed, in my opinion, solid genetic data to support them. Thus, anticancer drugs with more established targets would work as expected.
But Sheltzer says targeting the underperforming was part of the focus of the study. "Many anti-cancer drugs enter clinical trials based on very weak genetic evidence, and when you carefully evaluate them, the rationale for targeting particular genes evaporates."
In any case, he and his colleagues hope that the research will inspire further analysis of why many anti-cancer drugs do not help patients. "Research funding agencies are very interested in the next treatment, said Sheltzer, and are not enthusiastic about this research on the reproducibility and failure of certain drugs." If we want to accelerate looking for new effective treatments, maybe they should be.
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