Twenty years ago, the fight against cancer seemed to take a dramatic turn.
Traditionally, cancer doctors used raw weapons to fight the disease, often simply poisoning fast-growing cells, whether they were cancerous or healthy. Then a research team proposed a new strategy: drugs against proteins produced by cancer cells that seemed necessary for their survival.
Once upon a time, this drug, Gleevec, had a spectacular effect on patients with chronic myeloid leukemia. The following clinical studies, however, have usually led to disappointment. According to a study published earlier this year, only 3 percent of the cancer drugs tested in clinical trials between 2000 and 201
A study published on Wednesday in the journal Science Translational Medicine offers a reason for failure: Scientists pursue the wrong goals.
"I hope people will really wake up with the need to be much stricter," Dr. William Kaelin, a professor of medicine at Harvard University, was not involved in the new study.
Jason Sheltzer, a cancer biologist at the Cold Spring Harbor Laboratory in New York State, and his colleagues made the discovery when they were trying to develop a new breast cancer test.
] In certain forms of the disease, cancer cells produce a high level of a protein called MELK. Extremely high levels can mean poor survival for the patient.
Previous studies have shown that MELK is essential for the spread of cancer. In fact, researchers are already testing a breast cancer drug targeting the MELK protein.
Two students in dr. Sheltzer's lab, Ann Lin and Christopher J. Giuliano, used Crispr, the revolutionary DNA editing tool, to excise the MELK protein gene for MELK in cancer cells. The cells should have stopped growing, but to the scientists' surprise they did not.
"The cancer cells did not care," Dr. Sheltzer.
It was strange that the cells did not need an allegedly essential gene. Even stranger was when the scientists exposed the cells to the MELK targeting drug. The cancer cells were stopped anyway – although they lacked the gene targeted by the drug.
Dr. Seltzer wondered if he had just stumbled upon a particular case. So he expanded his research and did the same experiment with 10 other drugs. All were protein-targeting drugs that are currently in clinical trials.
With each drug, the scientists achieved the same results. Every supposedly essential protein turned out to be consumable in the cancer cells, but all these cells stopped growing when the scientists used the drug.
This type of mistake could lead to failures in clinical trials, Dr. Sheltzer. "When designing a clinical trial, you want to select the patients who are most likely to respond," he said. "This attempt can fail because you pick the wrong people to give you this medicine."
The mistakes that Dr. It may have been because of the unreliability of scientists searching for drug targets. "Many of the drug targets that are in clinical trials today were discovered using the best technology from five or ten years ago," he said, with high precision cancer targets. "Everyone thought we finally had the ghost in the lamp," Dr. Kaelin.
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With RNAi, scientists can create a molecule that blocks the production of a particular protein by cells. When blocking the production of a protein prevented the growth of cancer cells, scientists looked for a drug that also targeted this protein.
However, some critics asked whether RNAi is so precise. The technique may not only block one target protein, but also certain others. Dr. Sheltzer tested this possibility with one of the drugs in his experiment, OTS964.
The researchers gave the drug colonies of cancer cells with a distant target protein. Most were still dying – some were not.
The researchers sequenced the DNA of the surviving cells. It turned out that they had all the mutations in the same gene coding for a protein called CDK11B.
No one suspected that the protein was essential for the survival of cancer cells. The experiment of Dr. med. However, Sheltzer pointed out that the mutant cells survived because they had an altered form of the protein with which the drug could not interfere.
When the researchers excised the CDK11B gene, the cancer cells died – further evidence that the protein was necessary for the cancer cell.
Traver Hart, a cancer biologist at the MD Anderson Cancer Center in Houston, who was not involved in the new study, said scientists need to take another look at cancer drugs that are currently being tested by RNAi-driven bad targets the drug development pipeline, "he said.
That does not mean that it is meaningless to target essential proteins. Scientists just have to make sure they are looking for the right one.
The search for mutations in the genes of cancer cells may be one way to avoid false positives. Instead of relying on the presumption of what is a good target, cancer cells could speak for themselves.
"There is probably a whole universe of unexplored drug targets in the cancer cell," Dr. Sheltzer.