NEW DELHI :
Even as cancer races to become the world’s biggest killer, many of these seemingly effective drugs do not succeed in advancing to clinical use. They either turn out to be too toxic or just ineffective in humans.
Now, a new research led by American scientists has found that many of these potential cancer drugs do not actually act, as they were intended to do.
Though hopes of millions of patients are resting on cancer drugs, which are under various stages of clinical trials, the findings published in the peer-reviewed journal, Science Translational Medicine, may help explain what contributes to the high failure rate of new cancer therapies.
The team used the gene-editing tool, CRISPR, to examine the mechanisms of 10 cancer drugs which have been tested in human patients during various stages of clinical trials. The drugs have been used in at least 29 independent clinical trials involving more than 1,000 patients, but have faced similar problems during trials.
The drugs include citarinostat and ricolinostat, which are being tested against multiple myeloma, a type of blood cancer. The 10 drugs are designed to target one of the six proteins, which have been reported as important for the survival of cancer cells in more than 180 research publications.
However, the team demonstrated that the cellular protein, which they are targeting, is in fact, non-essential for survival and growth of cancer cells.
Researchers found that contrary to previous reports, the drugs did not actually kill the cancer cells by inhibiting their target proteins. Instead of killing the cancer cells by interacting with their intended molecular targets, they killed tumour cells through toxic, off-target effects. This led researchers to the conclude that the “drugs may not do what we think they do".
For example, the team found that the true target of the drug candidate OTS964, currently under trial, was not the ‘PBK enzyme’, which it was designed to target, but another enzyme named CDK11.
The study highlights the emergent 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.