New Delhi: Even as cancer races to become the world’s biggest killer, many of the seemingly effective cancer drugs do not succeed in advancing to clinical use. They either turn out to be too toxic or just ineffective in humans.
New research led by US scientists has found that many of these potential cancer drugs do not actually act as they are intended to do.
The findings published in the peer-reviewed journal Science Translational Medicine may help explain what is contributing to the high failure rate of new cancer therapies.
This is important because the hopes of millions of patients are resting on cancer drugs in various stages of clinical trials.
The team used the gene-editing tool CRISPR to examine the mechanisms of ten cancer drugs that have been tested in human patients during various stages of clinical trials. The drugs have been used in at least 29 different clinical trials involving a total of over 1,000 patients and have faced similar problems in trials. The drugs include citarinostat and ricolinostat, which are being tested against multiple myeloma, a type of blood cancer.
These ten drugs are designed to target one of the six proteins that have been reported in over 180 research publications as important for the survival of cancer cells.
However, the team demonstrated that the cellular protein they are targeting is, in fact, non-essential for survival and growth of cancer cells.
Researchers found that contrary to the previous reports, the drugs did not actually kill the cancer cells by inhibiting their target proteins. Instead, by interacting with their intended molecular targets, they killed tumor cells through toxic, off-target effects.
For example, the team found that the true target of the drug candidate ‘OTS964’ currently under trial was not ‘PBK enzyme’, which it is designed to target, but another enzyme named CDK11.
The study highlights the need to adopt more rigorous genetic approaches in preclinical trials to verify if future drug candidates work as intended.
“We suggest that there should be more stringent methods to identify the correct mechanism of action of potential cancer drugs and verify their targets before advancing them to the clinic. This would help in decreasing the number of therapies tested in human patients that fail to provide any clinical benefit," the team concluded.