By Bill Thomas | June 26th
One of the things that sets pediatric cancers apart from adult cancers is that pediatric cancers tend to be more rare, with patients under the age of 20 accounting for just 1% of all cancer diagnoses in the United States.
That might seem like a small percentage, but it translates to an estimated 14,910 children and adolescents diagnosed with cancer in 2024, according to the National Institute of Health. Consequently, pediatric cancers remain the leading cause of death by disease for children ages 1 to 14.
One reason for this is simply because the rarity of many pediatric cancers makes them difficult to study. It can take a long time to gather enough data from enough patients to be able to make statistically significant observations. It can take even longer to test those observations in order to successfully shed light on how pediatric cancers function.
Fortunately, Dr. Cody Nesvick, Assistant Professor of Neurological Surgery and Director of the Laboratory of Applied Epigenomics at the University of Pittsburgh, has had years to think about the best ways to help patients affected by pediatric cancers. In fact, he’s had a lifetime.
“Ever since I was a child I wanted to be a pediatric neurosurgeon,” Nesvick said. “I thought that everyone in the world wanted to be a pediatric neurosurgeon. I was surprised when I realized that was not the case.”
Nesvick’s lifelong drive to improve outcomes for children and adolescents diagnosed with cancers led him to a neurosurgery residency at the Mayo Clinic, which he began in 2016. While there, he began studying atypical teratoid rhabdoid tumor (ATRT), a rare and aggressive form of pediatric brain cancer. Specifically, he began studying what it is that sets ATRT apart from other pediatric cancers.
“Typically we think about cancer as a heterogeneous disease, one where there are lots of genetic changes that collaborate to give rise to a highly malignant tumor,” Nesvick said. “Pediatric cancers are different; they are often more simple from a genomic standpoint, having fewer molecular changes. Even amongst pediatric cancers, though, ATRT is unique in that it the only unifying molecular feature in most cases is a loss or mutation of SMARCB1.”
SMARCB1 is a gene that encodes subunits of the SWI/SNF complex involved in chromatin remodeling. SWI/SNF plays a critical role in regulating the activity of enhancers, DNA elements that boost gene expression. In certain settings, when SMARCB1 disappears or is disrupted, it can cause cells to become malignant, ultimately resulting in tumor growth.
In 2023, Nesvick received grant funding from Pediatric Cancer Research Foundation to study how SWI/SNF interacts with cell differentiation transcription factors, proteins that activate the expression of genes necessary for cells to grow and differentiate in a normal fashion. Now, three years later, Nesvick’s findings, published in Neuro-Oncology, could help revolutionize the way ATRT is treated.
“What we found is that these two classes of molecular complexes, SWI/SNF and transcription factors, are actually both necessary to activate the gene expression changes necessary for a cell to differentiate. This is important because it changes the different ways that we can potentially treat these tumors, as these transcription factors are still expressed even in the absence of SMARCB1,” Nesvick explained.
“We found that, in the absence of SMARCB1, those transcription factors get recruited to genes that are necessary for cell survival, and therefore they might be therapeutically targeted.”
Nesvick’s findings represent a significant step forward in science’s understanding of how ATRT functions, identifying a vulnerability in the disease that further research may be able to leverage to maximize treatment efficacy.
“That is going to be an ongoing area of investigation. Transcription factors are inherently difficult to target, but fortunately we were able to use drugs that indirectly inhibit activation of the transcription factors,” Nesvick said, noting that while they’ve seen positive results using the FDA-approved drugs trametinib and verteporfin, there have also been efforts to explore SWI/SNF degraders.
“I think that more directly targeting these residual SWI/SNF complexes using other small molecule inhibitors or nanoparticle-based technologies is going to be an important avenue of research over the next 5 to 10 years.”
Thanks to the innovative work of Cody Nesvick and other PCRF-funded researchers, the future of pediatric cancer treatment is looking brighter every day. If you would like to help us continue powering research project that target rare cancers with low survival rates and develop more effective, less toxic treatments, please consider becoming a donor.
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