From Critters to Kids: Finding a Cure for Childhood Cancer

I grew up loving the movie The Fault in our Stars, which is about a 16-year-old’s battle with thyroid cancer. I thought it was a heartfelt but rare story, and only recently understood the traumatic nature of pediatric cancer on kids and their families. Every year, around 400,000 adolescents, aged 19 and under, suffer from cancer worldwide. Past infancy, cancer is the leading cause of death from disease for children in the U.S. The collection of diseases is known to be caused by genetic mutations, or changes in DNA. 

Leukemia, the most common childhood cancer, is a type of blood cancer. One of the biggest challenges in researching and treating childhood cancer is that many treatments are modeled after the adult version of the disease, causing debilitating long-term side effects in children. The development of preclinical pediatric cancer models that accurately represent childhood cancer is necessary. Designing targeted therapies can improve outcomes for pediatric patients. 

The most common models for pediatric cancer research are mice. Scientists at St. Jude, a leading pediatric cancer research institution and hospital, have discovered a short-term treatment with the drug ruxolitinib, which prevents B-cell acute lymphoblastic leukemia (B-ALL) in mice that have a genetic predisposition to the disease. Their research indicates that this therapy could possibly work for other types of cancers since precancerous cells are a common feature in a variety of cancers.

Stanford University pediatric and adult cancer researcher Dr. Julien Sage works with the Retinoblastoma (Rb) protein, which is a major cancer-causing protein when it is mutated. 

“I work on mouse models with Rb mutations and try to replicate in mice what happens to children when they have an Rb mutation,” said Dr. Sage. “Children usually have both Rb alleles mutated and we try to model that.” 

The cause of childhood cancer usually mimics adult cancers, but according to Dr. Sage, “adult tumors are caused by many accumulated mutations due to lifestyle or genetics but pediatric tumors are due to fewer cancerous mutations in stem cells which can spread really fast.” 

While Dr. Sage’s lab uses mouse models to study the Rb protein, some studies use mice for developing targeted treatments that attack cancer metabolism. Scientists at the Institute of Cancer Research in London, used mouse models to test 228 different compounds against neuroblastoma cells in the lab. They discovered various drugs that were effective for 80% of the mice. Besides mice, the zebrafish is another animal that’s used as a preclinical model for gene and drug discovery in pediatric cancer. 

Solid tumors are commonly studied by transplanting human tumors into mice. This was attempted as early as 1975 by Lawrence Helson and his research group from the National Institutes of Health. He injected human neuroblastoma cell lines into immunodeficient Swiss-Webster mice to study the tumors, as they don’t reject them. Other mouse models have been used to study the effects of gene mutations. The research group of Barr FG studies the effect of mutated transcription factors (proteins regulating gene expression) on pediatric cancer. Dr. Sage’s lab, as mentioned above, works with genetically engineered mouse models where they recreate tumor mutations with altered genes or deletions as needed to replicate actual cancers. They also sometimes take tumor samples from the clinic and transplant them into mice to study brain tumor therapeutics. Their biggest challenge in studying pediatric brain tumors according to Dr. Sage is that the “mouse brain is not very similar to the human brain.” 

Mouse models have also been used to study metastasis (the spread of cancer). These models have not been very successful because different types of cancer behave differently and it is difficult to constantly monitor the metastasis during the study. Mouse models are also used to study the treatment of cancer with immunotherapies, but are not always capable of accurately predicting the outcome in humans. 

“Immunotherapies don’t work as well in pediatric tumors due to fewer mutations and fewer T cells getting activated compared to adults,” said Dr. Sage “At the end of the day, animal models are not the real thing so it is important to be aware of the reality.” 

At the same time, animal models in pediatric solid tumor research appear to have made great strides. 

“We can now understand how cancer works and have learned about therapeutics but obviously there are gaps,” said Dr. Sage. “The mechanism of tumor response is something models have helped with. We understand why some genes give rise to some cancer types despite being universally present like Rb better and hope to develop better therapeutics and minimize long-term effects on pediatric patients.” 

Animal models have helped tremendously in the study of pediatric cancers and the future looks promising.