Cancer therapies often fail to work when tested in clinical trials. As a result, a startling 97 percent of drugs designed for specific cancer treatments do not receive approval from the Food and Drug Administration. Now researchers say they may have figured out part of the reason why.
In a new study out Wednesday in the journal Science Translational Medicine, scientists report many cancer drugs don’t work the way their designers assumed they did. The discovery may explain why so many cancer therapies fail to benefit patients.
“Our study showed us that a potential issue with the cancer drug development pipeline is that the ways in which some of these new cancer drugs work is incompletely understood,” one of the study’s lead authors, Chris Giuliano, said in a press briefing.
Off-target, Still Working
In two previous studies, Giuliano and co-author Ann Lin showed a protein thought to be essential to multiple kinds of cancer actually had no effect on cancer growth. This protein was the target of a drug therapy aimed at stopping certain kinds of cancer. But, even when the duo removed the protein from cancer cells the drugs were still effective. In other words, the drugs worked, but not in the way they were purported to.
In the new study, the researchers set out to determine whether the same thing would happen with other anti-cancer drugs. The team tested 10 cancer meds that have been in clinical trials or are close to entering clinical trials. The drugs acted on various proteins that cancer cells were thought to need to grow. So, the researchers used the gene editing technology CRISPR to remove the proteins each therapy supposedly targets from cells taken from a variety of cancers.
“We’re very surprised to find that when we eliminated these proteins from the cancer cells, that the cancer cells continued to grow just fine in spite of what had previously been published,” cancer biologist Jason Sheltzer, who led the research, said at the press briefing. Sheltzer mentored Lin and Giuliano, who completed much of the new work as undergraduate researchers in Sheltzer’s lab. The two are now pursuing graduate studies at Stanford and the Massachusetts Institute of Technology, respectively.
The findings show that targets of precision medicines often aren’t essential for cancer cell growth, Sheltzer says.
New Cancer Therapies
As in their previous research, the scientists went on to show that the drugs were still able to kill cancer cells even after the team had completely removed the drugs’ targets. The results proved the therapies must be killing the cancer cells in a different, unknown, way says Sheltzer.
Despite the shocking findings, Sheltzer sees the results as an opportunity. “We can now take these drugs and we can see if we can figure out what they actually do in cancer cells,” he said. “And so if we are able to successfully do that then we might find new vulnerabilities in cancer cells that we can target or new ways to identify the patients who are most likely to respond to a particular therapy.”
The researchers were able show this is possible. In the new study, they determined the true target of an anti-cancer therapy called OTS964 is a protein called CDK11, not one called PBK, as previously suspected. Before this, there were no known drugs that targeted CDK11. The finding may help make clinical trials for cancer therapies more successful by determining which patients might respond well to CDK11 therapy.
“Knowing how your drug is working to kill the tumor is the only way to predict which patients might benefit from a given treatment,” Giuliano said.
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