Why biology demands a different playbook for kids with cancer

Treating cancer in a child is not a scaled-down version of treating cancer in an adult. It is a fundamentally different landscape that reshapes how we discover targets, diagnose disease and design therapies. Pediatric cancers follow their own biological rules, and understanding this distinction is the foundation of effective research. For Charles W.M. Roberts, MD, PhD, executive vice president and St. Jude Comprehensive Cancer Center director, this difference underpins his approach to discovering the next generation of therapies for children.

A different disease from the start

Roberts did not intend to become a pediatric oncologist. “I had planned to do adult oncology,” he recalls. However, after a pediatric rotation in medical school, he witnessed children confronting cancer and families navigating uncertainty. “As soon as I completed that rotation, I switched my focus.”

Now a pediatric oncologist, Roberts notes that childhood cancer is biologically distinct from adult disease. Adult cancers usually appear after years of accrued damage to cells from environmental exposures such as carcinogens, ultraviolet light and lifestyle choices. Over time, cells collect thousands of mutations that can then turn cells cancerous. Childhood cancers, by contrast, often emerge when developmental processes misfire.

Roberts explains, “In children, the mutational burden is much lower; their tumors form because a small number of mutations cause normal development to go off track.” 

Historically, that difference may not have mattered much for treatment. Traditional chemotherapies attack rapidly dividing cells regardless of what is fueling their growth, but traditional chemotherapy is not curative, and it causes short- and long-term side effects.

However, a shift toward more precise therapies rooted in the biological basis of disease laid bare a new problem: Targeted therapies developed for adult cancers often have little or no benefit for childhood cancers because the underlying mechanisms are different.

Precision medicine exposes the gap

Modern targeted therapies focus on specific genes or molecules, many of which were discovered in adult cancers; however, 55% of the gene mutations in childhood cancers are not present in adult cancers. “This means the old approach of therapies trickling down from adult cancer treatment to childhood cancer treatment won’t work to target these mutations,” Roberts says.

Immune checkpoint inhibitors further illustrate this mismatch. These therapies work when cancer cells have many genetic changes that the immune system can spot. That approach suits many adult cancers, but pediatric tumors, with far fewer mutations, present little for immune cells to recognize. As a result, checkpoint inhibitors have shown limited benefit in children.

Still, that does not mean there is no genetic overlap. Nearly 45% of mutations seen in childhood cancers are also found in adults. “In those cases, we can learn from what has been studied in adults, and our studies of childhood cancer can inform adult therapy,” Roberts notes.

Roberts’s laboratory demonstrated this bidirectional learning through studies of the SWI/SNF chromatin-remodeling complex, mutated in more than 20% of cancers. Roberts used aggressive pediatric malignant rhabdoid tumors to study the impact of SWI/SNF mutations since a mutation of a specific component of SWI/NSF, the SMARCB1 gene, causes these tumors. His lab discovered that disruption of SWI/SNF changes gene expression and normal cell-development programs.

That work played a role in helping understand adult cancers with the same alterations and contributed to FDA approval of an EZH2 inhibitor to treat SMARCB1-deficient cancers in children and adults: a powerful example of how childhood cancer research can accelerate therapeutic innovation for all ages.

New therapeutics frontiers

This kind of insight has opened the door to a wave of new therapeutic approaches now taking shape at St. Jude.

One example is targeted protein degradation. Instead of blocking harmful proteins, degraders mark them for disposal by existing cellular machinery. In the Department of Chemical Biology & Therapeutics, research led by Taosheng Chen, PhD, PMP, recently used a drug called proteolysis-targeting chimeras (PROTACs) to attach to a hard-to-reach “hidden pocket” on a protein. This discovery revealed a new way to interrupt the signals on which cancer cells rely.

Another approach is immunotherapy. Checkpoint inhibitor drugs have not worked well in pediatrics, but the Center of Excellence in Pediatric Immuno-Oncology at St. Jude is moving new targeted immunotherapy approaches forward. Chimeric antigen receptor (CAR) T cells are a type of immunotherapy that uses a patient’s cells to identify and destroy cancer cells. CAR T–cell therapy for relapsed childhood B-lineage leukemia has had a major impact. What was once a last-resort option can now produce lasting remissions in children whose cancers repeatedly progressed and were considered incurable. Lessons from pediatric trials inform the design of engineered T cells that may benefit adult patients as well.

Other emerging modalities include RNA-based therapies and epigenetic reprogramming. At St. Jude, investigators, including Roberts and colleagues, are increasingly exploring RNA

therapeutics as a new frontier. These tools can modulate gene expression, correct dysregulated pathways or silence cancer-driving signals with unprecedented precision.

Together, these approaches signal a new era of treatments designed around the fundamental biology of childhood cancer. “Importantly, these approaches may unlock new possibilities for treating other devastating childhood diseases rooted in specific genetic mutations,” Roberts states.

Turning differences into strengths

Even when biology points clearly toward new therapeutic avenues, the economics of new drug development often halt progress. Pediatric cancers account for a small fraction of diagnoses and offer limited commercial return. For drug companies, there is little financial incentive to create therapies for rare childhood cancers, especially when adult cancers represent larger markets.

“The usual economic models fail childhood cancers,” Roberts says.

To bridge this gap, St. Jude has invested in internal initiatives that support preclinical development, target validation and early-phase clinical trials. These programs are not meant to replicate pharmaceutical pipelines but to ensure that promising ideas rooted in the biology of childhood catastrophic diseases have a viable pathway toward early-phase testing.

“In many ways, the distinct biology of childhood cancers gives us a chance to rethink what’s possible,” Roberts says. “When we design therapies specifically for children, we not only improve their chances; we often uncover insights that help adults too.”