Promising Anti-Cancer Molecules Lead Double Life
Sylvester research offers new insights that could make recaglates more effective.
In a study published in Cell Reports, researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown that emerging anticancer drugs called recaglates do more than previously thought.
In addition to inhibiting production of some cancer-driving proteins – as expected – these drugs boosted other proteins, generating uncertain biological consequences. While these surprising results muddy the waters on recaglates, they also suggest that these drugs could be combined with other therapies to make them more effective.
“Recaglates are unique because they target a specific translation initiation process, which is how the cell turns genetic information into proteins,” said Associate Professor Jonathan Schatz, M.D., senior author of the paper. “They target this process in a way that turns down translation without turning it off, in a way that cancer cells find particularly toxic. We were amazed to find that, in some cases, recaglates also turn translation up.”
Controlling protein translation initiation could be a promising option to treat multiple cancers. Many current drugs inhibit a single cancer-driving cell signaling pathway, giving tumors opportunities to switch pathways and escape treatment. Hitting the cell’s translational machinery could significantly narrow a malignancy’s options.
“These signaling pathways have redundancies, overlaps, and feedback mechanisms that make it easier for cancer cells to ‘rewire’ and get around a single target being inhibited,” said Dr. Schatz. “However, translation initiation is a convergence point for many of these signals, potentially making it more difficult for cancer to develop resistance.”
To better understand these mechanisms, the research team used mass spectrometry and other methods to generate a more global picture of the proteins being synthesized and how recaglates affect that output. Mass spectrometry creates its own challenges, as the method produces enormous amounts of data. Dr. Schatz noted that co-authors Associate Scientist J.J. David Ho, Ph.D., and Professor Stephen Lee, Ph.D, were essential to accurately interpret the data.
In another surprise, the team found that the protein eIF4A, the primary recaglate target, probably plays no role in the transcriptional remodeling. In other words, these drugs have another important target yet to be identified.
“There are more cards to turn over,” said Dr. Schatz, “and that will be a major emphasis going forward.”
While this study does not fully capture how recaglates affect cellular translational machinery, it does provide a much broader picture and points the way to future studies.
“Our data show that these drugs are not just inhibitors, they’re actually remodelers,” said Dr. Schatz. “They have a much more complex effect on translational output than simple inhibition. Though these results give us mixed news, they also give us mechanisms we can pursue to maximize recaglate efficacy. But first we need to understand the mechanisms.”
On a therapeutic level, the research showed that recaglates also activate the translation factor eEF1?1, which boosts synthesis of several proteins. This response may reflect cancer cells adjusting their environment to survive treatment. If that is the case, cancers may become reliant on this mechanism, providing a new angle to destroy them.
“We’ve discovered several new things about the way recaglates work,” said Dr. Schatz. “The next step is to take these findings into specific cancer types and figure out how we can use these mechanisms to deliver long-term benefits for patients.”
Tags: cancer research, Dr. Jonathan H. Schatz, Sylvester Comprehensive Cancer Center