Does Missing RNA Hold the Key to Treating Brain Cancer?

By Lauren Ingeno

The Findings

Researchers at Children’s Hospital of Philadelphia discovered a new immunotherapy target for treating pediatric high-grade glioma, a fast-growing and aggressive brain tumor. They found in a preclinical study that during a process called alternative splicing, tumor cells often skip tiny sections of RNA called microexons, which are parts of the NRCAM and related genes. The researchers were then able to design an antibody that specifically recognizes this altered NRCAM gene to treat cancer.

Why It Matters

Pediatric high-grade gliomas are some of the most chemotherapy-resistant and often surgically unresectable childhood cancers. Children affected by these aggressive brain tumors nearly always succumb to the disease within 10 months of their diagnoses. Despite decades of clinical trials, there are no effective treatments for these patients, underscoring the need for new immunotherapies.

Several targets for chimeric antigen receptor (CAR) T-cell therapy have been developed. However, these emerging therapies are currently not curative for pediatric high-grade glioma, which underscores the need for additional targets.

Who Conducted the Study

Andrei Thomas-Tikhonenko, PhD, Chief of the Division of Cancer Pathobiology, was the study’s corresponding author, and Priyanka Sehgal, PhD, a research scientist in the Thomas-Tikhonenko Laboratory, was the study’s first author.

How They Did It

CHOP researchers focused their efforts on alternative splicing — a process in which cells make many different proteins from the same gene by rearranging exons, the building blocks of messenger RNA. They hypothesized that messenger RNAs are cut and reassembled differently in cancer cells compared to normal brain cells, and these alterations could produce new highly selective targets for T cell-based immunotherapies.

Using high-throughput RNA sequencing, the researchers discovered that two specific NRCAM microexons (exons 5 and 19) were missing in nearly all glioma samples. When studied in cell and small animal models, they found that the shortened version of NRCAM was essential for cancer cell migration, invasion, and growth.

The team then developed an antibody that specifically recognizes this altered NRCAM, but not the normal version found in healthy brain cells. When they used this antibody to "tag" the cancer cells, the engineered T cells were able to recognize and kill them with great specificity.

Quick Thoughts

“Microexons are often overlooked because it's easy to miss them in sequencing datasets, but we were motivated to look at them more closely,” Dr. Thomas-Tikhonenko said. “We hypothesized that the genes expressed in gliomas and healthy brains might be the same, but splicing of microexons might work very differently. That proved to be the case.”

What’s Next

The researchers plan to expand their preclinical research and refine an immunotherapy that could be explored in a clinical trial. 

Where the Study was Published

The researchers’ findings were published in Cell Reports. The study was funded by the CureSearch for Children’s Cancer Foundation Acceleration Initiative and by the National Institutes of Health. Read more in a CHOP press release.