Researchers find “smart drugs” might not be so smart

Yale researchers have found that for some people, the expensive cancer medications called “smart drugs” might not be so smart after all.

The medications are called “smart drugs” because of their ability to stop tumors by targeting key drivers of cancer cell growth, but the drugs are not effective in some patients. In two connected studies, Yale School of Medicine researchers studied one such driver, the EGF receptor (EGFR), and discovered that a decoy receptor might be limiting the amount of drug that gets to the intended target.


“We know that smart drugs like Cetuximab are not always effective in the cancer cells they’re supposed to target because there are no positive predictive markers for selecting the patients who will benefit from treatment with EGFR-targeted therapies, including EGFR itself,” said lead author Nita Maihle, professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences and of Pathology at Yale School of Medicine. “Why would a patient be given an expensive drug if it doesn’t work? Our studies provide new insight into this paradoxical EGFR testing conundrum.”


In a study recently published in the journal Cancer, Maihle and her coworkers isolated a protein from human blood that looks like EGFR, but is actually a related variant called serum sEGFR. They revealed that Cetuximab binds equally as well to serum sEGFR as it does to the projected EGFR cancer target.


The study results allowed the researchers to see that sEGFR might act as a decoy receptor in the blood of cancer patients, binding up Cetuximab and thus limiting the quantity of Cetuximab that actually gets to the target.


The limitations might provide an explanation for the failure of two large phase III clinical trials on Cetuximab in colorectal cancer patients, since serum sEGFR concentrations are extremely variable in cancer patients. These studies propose that serum sEGFR should be measured and considered prior to treatment with Cetuximab. Additional research has reinforced this concept by showing that serum sEGFR concentration changes in response to treatment with Cetuximab.


In the research group’s second related study, published online in the current issue of the journal Biochemistry, the team showed that newly developed reagents to measure sEGFR in blood and other human tissues can detect a second unrelated cell surface protein in tumor cells: alpha-5 integrin.


“This important finding suggests that the naturally occurring sEGFR protein may play a complex role in cell adhesion and migration-two cellular processes important in the spread of cancer,” said Maihle, who is a member of Yale Cancer Center. “Together these studies demonstrate an unanticipated level of complexity in EGFR signaling and assay development, and suggest new ways to overcome current challenges associated with clinical testing for this important cancer target.”


The studies were funded by the National Cancer Institute, Susan G. Komen for the Cure, and the Marsha Rivkin Center for Ovarian Cancer Research.

Hopefully in the future cancer researchers will be able to educate the drugs and make them “smarter”. Apparently it takes smarts for cancer drugs to have an impact on a patients’ condition.