Pediatric Cancer and the ‘RACE’ for Equitable Treatments

Charles River’s patient-derived xenografts are playing an important role in finding new drugs that are more equitable for children with cancer

There is no doubt significant strides have been made in the treatment of childhood cancer. More than 50 years ago, it was rare for a child to survive leukemia, the most common type of childhood cancer. Today, we are seeing a 90% cure rate, with many children going on to live happy and productive lives.

Despite these strides, cancer remains the leading cause of disease-related death in children and adolescents. Every year, about 19,000 children and adolescents ages 0-15 in Europe and the US are diagnosed with cancer. Approximately one in four of these young patients cannot be cured with current standard therapies and do not survive the disease.

Could animal avatars—where a tumor from a child is regrown in an animal—provide a solution? The European academic consortium known as Innovative Therapies for Children with Cancer or ITCC thinks so and recently launched the ITCC-P4 project to develop patient-specific laboratory models for the most common high-risk childhood cancers, and relapsed cancers that are currently undertreated. Charles River Laboratories is one of their many industry partners, and will be reporting on some of its research at the upcoming AACR meeting in San Diego opening April 5.

The ITCC-P4 follows a 2020 legislative amendment to the Research to Accelerate Cures and Equity (RACE) that all cancer drugs be tested in children if the mechanism of action is relevant to a childhood tumor. The European Union has adapted its guidelines to meet this goal as well.

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The most difficult pediatric tumors to treat

While all childhood cancers are difficult to bear, tumors of the brain and spinal cord—referred to collectively as Central Nervous System cancers—are among the hardest to treat. The average survival rates for children diagnosed with glioblastoma, for instance, are 12-18 months; only 25% of children survive more than a year.

With brain and spinal cord tumors the second most common cancer seen in children, advances in research and innovative therapies are crucial to improving outcomes and reducing mortality. One way to do that is by making sure the models being used to develop new drugs stand up to rigorous preclinical tests.

Scientists agree that the solution to this problem lies in finding customized models that are suited for finding drugs that work in the youngest cancer patients, and shedding the assumption that an adult with brain cancer or leukemia is the same as in a child. In fact, pediatric tumors have different genomic drivers and phenotypes than adult tumors; while adult tumors typically acquire a lot of cell mutations in a stepwise fashion, in children it’s more of single switch that is difficult to shut off. So, tailoring an adult cancer drug to a child isn’t as easy as it sounds. Finding the right preclinical platform, however, has been a major roadblock for oncology drug developers.

“Until now, neither the pharmaceutical companies nor the pediatric oncology research community have been sufficiently prepared because, especially for high-risk tumors, there were very few and poorly characterized and standardized preclinical laboratory models to conduct systematic drug trials, said ITCC President Gilles Vassals on the consortium’s website.

Charles River’s PDX portfolio is playing an integral part of getting us toward more translatable pediatric models. Charles River’s Freiburg, Germany site, which has three decades of experience working with PDX models representing all major histotypes and tumors, has access to more than 200 annotated, well-characterized, RACE-compliant pediatric PDX models that will help accelerate the development of new pediatric cancer drugs. In the future, digital twins—AI-assisted human disease computer models—will be created from PDX models, too.

In addition to volume, the tumor grafts that Charles River uses in its PDX models are also described as having a “low passage rate” – science speak for the number of times the cell cultures used in the grafts need to be subdivided into daughter cell colonies. This goes a long way toward ensuring the cells do not take on different behaviors or characteristics, and the original tumor characteristics are conserved. Typically, most cell lines reach a point where they need to be transferred from one culture to another in order to keep expanding. However, the more you subculture, the greater the risk of genetic drift and incompatibility. Charles River’s rate is six, which means the cells are genetically resistant to pressures that can result in changes to the cell populations over time.

At the annual AACR meeting in San Diego, the ITCC-P4 consortium will be sharing some of the progress being made in customizing treatments for children. The study conducted by Charles River and three ITCC-P4 project partners – the Institut Curie in Paris, Medical University Wien in Vienna and Deutsches Krebsforschungszentrum (German Cancer Center) in Heidelberg—tested 10 orthotopically implanted pediatric brain tumor PDX models in highly immunodeficient mice. Research like this will hopefully go a long way toward finding real solutions for children unfortunate enough to be dealt a cancer blow.