A study published in the journal Cell Chemical Biology explains the reason why some cancer drugs under development fail in laboratory experiments, which is “insufficient genetic analysis.”
“These drugs are so toxic that patients can't take them safely, or they can be taken but they don't actually shrink the patient's tumor,” said lead study author Jason Sheltzer, an assistant professor of surgery and genetics and a member of the Yale Cancer Center.
Uncovering the mechanisms behind a misprescribed drug can shed light on its poor performance in clinical trials.
Most cancer drugs also fail to obtain approval from the US Food and Drug Administration. To understand why, Dipanjan Bhattacharjee, Ph.D., and Jawiria Bhakar of Scheltzer's lab, studied a p38a inhibitor drug called ralimetinib.
“When we tested this drug in our lab, we found that it targets a different pathway,” Sheltzer said. None of the patients responded because cellular sensitivity to ralimetinib showed the strongest association with EGFR inhibitors.
He added: “Often, researchers develop a drug, and they see that it kills cancer cells. That will be enough to motivate the trial. But there is no ‘genetic understanding’ of how or why cancer cells are killed. Without this genetic understanding, you don’t actually know.” "Which cancer patients should you give it to, because you don't know what biomarkers or genetic changes to look for in the patient's tumor in order to give them this drug."
Scientists need a multimodal approach to target the underlying mechanisms of disease.
“If we had had this genetic understanding of the drug sooner, it might have been given to a different group of patients who were more likely to respond,” Sheltzer said.
Scientists can gather evidence using a range of tools, including the revolutionary CRISPR technology, drug genotyping, and structural assessment.
Although more testing is needed, the approach that prioritizes genetics has broad applications in the fight against cancer. Genetic analysis in a multidisciplinary setting is key to improving the success rate of new treatments.