MSK Research Highlights, August 13, 2024

New research from Memorial Sloan Kettering Cancer Center (MSK) found patients with non-small cell lung cancer brain metastases may benefit from up-front stereotactic radiosurgery; identified a connection between antibiotic use and autoimmune diseases; and uncovered a previously unknown structural role for messenger RNAs in the cytoplasm of cells.

Patients with non-small cell lung cancer brain metastases may benefit from upfront stereotactic radiosurgery

For patients with non-small cell lung cancer that has spread to the brain, targeted therapies called tyrosine kinase inhibitors (TKIs) can be effective at shrinking these tumors. Another treatment for these brain metastases is a type of radiation therapy called stereotactic radiosurgery (SRS), in which powerful and highly targeted radiation is delivered in a focused way to brain metastases, with the help of sophisticated imaging technologies. Traditionally, SRS was the first treatment for brain metastases, but recently there has been a growing trend toward deferring up-front SRS in favor of TKIs. However, these approaches have never been directly compared in a clinical trial.

In a multicenter, retrospective study, a team led by Luke Pike, MD, DPhil, director of brain radiation oncology at MSK, looked at whether giving SRS at the same time as targeted therapy may make treatment more effective. The team reviewed data from 200 patients who received TKIs alone and 117 patients who received TKIs and SRS. They found that although adding SRS to drug treatment did not help patients live longer, it extended the time it took for their disease to progress. This is particularly significant because the patients who got SRS tended to have larger tumors. Based on the findings, the researchers conclude that patients with brain metastases may benefit from having SRS in addition to drug therapy up-front, especially those with larger tumors.

Dr. Pike is now working to initiate a randomized phase 2 clinical trial that will selectively use SRS for patients receiving TKIs that target the EGFR gene — the most commonly altered subtype of non-small cell lung cancer, and one with a high likelihood of spreading to the brain. “Instead of treating all patients up-front, this trial seeks to selectively add SRS to the care of those patients who are likely to be at the highest risk of their brain metastases growing and causing harm, while de-intensifying treatment for most patients,” he says. “We hope that this will result in meaningful improvements in quality of life for our patients living with brain metastases.”

Read more in the Journal of Clinical Oncology.

New evidence for a connection between antibiotic use and autoimmune diseases

Scientists at MSK have uncovered a new connection between depletion of gut bacteria caused by antibiotics and the development of autoimmune diseases. The study, conducted in mouse models, shows that clearance of dead cells — which is necessary for health and the prevention of autoimmune responses — involves not only local signals from within a tissue but also distant signals from other parts of the body, such as the gut. The study looked at mice whose gut bacteria had been depleted by antibiotics and found that immune cells in the abdomen (large peritoneal macrophages) were not clearing out dead cells as well as they should be. When butyrate — a short-chain fatty acid produced by gut bacteria when they breakdown dietary fiber — was given to the mice, it improved the ability of the macrophages to clear out the dead cells. Using a variety of techniques, the team further uncovered key genes and transcription programs involved in the process. They also found that cell clearance remained impaired for a time after the antibiotics were stopped. The study, overseen by immunologist Justin Perry, PhD, a member of the Sloan Kettering Institute and led by postdoctoral fellow Pedro Saavedra, PhD (who now heads a lab at Northeastern University), also looked at the phenomenon in a mouse model of lupus. They found mice treated with antibiotics had significantly worse disease symptoms. Overall, the findings suggest that gut bacteria-produced butyrate and its impact on the body’s ability to clear out dead cells may be a key factor linking antibiotic use to autoimmune disease. Read more in Nature Metabolism.

New research uncovers structural role for messenger RNAs in the cytoplasm

A new study from the lab of Christine Mayr, MD, PhD, at MSK’s Sloan Kettering Institute has unveiled a novel structural role for mRNAs in the cytoplasm. The research introduces the FXR1 network, a messenger RNA-protein network that plays a pivotal role in cellular signaling and organization.

The FXR1 network is formed by FXR1-mediated packaging of exceptionally long messenger RNAs expressed in cells — which are 3-6 times longer than most mRNAs and make up about 10% of the total.

“Think of the FXR1 network as a bustling hub where FXR1 and messenger RNAs interact and help each other to assemble,” says study first author Xiuzhen Chen, PhD, a postdoctoral researcher in the Mayr Lab who received a 2022 Kravis Women in Science Endeavor (WISE) fellowship. “More importantly, signaling proteins that cannot bind RNAs directly get attracted into the network by FXR1. This way, the FXR1 network acts as a hub where signaling proteins can easily find each other.”

The findings show that messenger RNAs do more than just encode proteins, they also serve as structural components that organize signaling reactions in the cell, Dr. Mayr adds. “This discovery opens up new avenues for understanding cellular processes and the molecular basis of diseases like Fragile X Syndrome,” she says.

Mutations in FXR1 are similar to those found in the closely related gene FMR1 that are associated with Fragile X syndrome, a genetic disorder that affects cognitive development, Dr. Mayr notes. These mutations disrupt the FXR1 network and prevent signaling reactions. This disruption highlights the network’s importance in maintaining cellular functions. The principles revealed in the study provide a new path for understanding human diseases stemming from dysfunctional RNA binding proteins by showing that in addition to their well-studied functions, messenger RNAs can also be organizers of signaling reactions. Read more in Cell.