Q&A: Crystal Mackall, John Maris on Pediatrics

New therapies and partnerships strive to accelerate progress in childhood cancers

“Just 5 years ago we thought that applying next-generation sequencing technology to a large number of pediatric cancers would provide novel insights into druggable pathways, but that hope was not fully realized,” says John Maris, MD, director of the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “Very important discoveries have come out of these large-scale efforts, but as yet not much in terms of tangible deliverables to patients. That's part of the motivation for taking new approaches to develop treatments.”

Maris and Crystal Mackall, MD, chief of the Pediatric Oncology Branch of the National Cancer Institute (NCI), lead a Stand Up to Cancer (SU2C)/St. Baldrick's Foundation Dream Team that will develop immunotherapies for childhood cancers. The two talked with Cancer Discovery's Eric Bender about some challenges in pediatric cancer research.

What's the state of progress in childhood cancer?

Mackall: The last 20 years have brought with them an explosion of information about the biology of cancer, and pediatric oncology research has been no exception. But the translation of these biologic investigations to new therapies for patients has not been as robust in pediatric cancer as it has been in adult cancer. Some of that is because these tumors are simply less mutated. There are fewer abnormalities in the pediatric tumors than in the adult tumors, and many of the abnormalities are epigenetic or driven by transcription factors that remain generally undruggable.

How does the rarity of pediatric cancers affect funding?

Mackall: Any one of our diseases is a rare disease, but I do not believe that the funding has been sufficient. People often say that about 4% of cancers are pediatric cancers, so about 4% of the NCI budget should be for pediatric cancers. We have tried to argue that the basis of this calculation may be flawed, given the years of life lost for childhood cancer, and because what we've learned about childhood cancer often has had implications for adult cancer.

Are drug companies investing in trials for pediatric drugs?

Maris: Pharmaceutical and biotech companies are moving away from the blockbuster model to drugs that will have potent influences on small subsets of adults. While this is a new model for adult cancer, it is the model we have always been forced to work with in pediatric oncology. We are hopeful that relative rarity will ultimately become less of an issue than it used to be. In our SU2C grant, we have several industry partners developing drugs that will be applicable to a relatively small number of patients.

Mackall: The idea that small markets can't be profitable is challengeable today. One example is the development of the anti-GD2 antibody in neuroblastoma, which was tested all the way through a definitive phase III trial with academic funding. When a company jumped in at the end of the phase III, all the risk was gone, and the model was there to make a profit.

Public/private partnerships, and bringing some drug development into academia, are part of the SU2C model, where the focus is primarily based on deliverables.

But we also need incentives for drug development for childhood cancers, where the number of patients with certain diseases is minuscule. Government agencies, both in Europe and in the United States, have recognized this need for incentives. We are still learning which incentives work and how best to configure them.

What are some challenges ahead in large-scale genomics?

Maris: There are three big unknowns.

One unknown is our lack of understanding of what is happening in the 98% of the genome that isn't protein coding and that hasn't been thoroughly investigated to date. Another unknown is the translational relevance of the important role chromatin biology and methylation and acetylation changes play in pediatric cancers. Epigenetics is such an important part of normal tissue development, and these diseases fundamentally arise due to both genetic and epigenetic alterations.

The third unknown is how the host genome is shaping the cancer phenotype. We know that if you're born with a mutation in p53 or BRCA1 you're likely to develop cancer. But it's also clear that in most pediatric patients there is genetic underpinning due to a confluence of both rare mutations and common polymorphisms, each of which has a relatively small effect. However, genes deregulated by these low potency initiating events can be of critical importance in the established cancer, and these nonmutated pathways may be targeted therapeutically.

How might patient care change in the next few years?

Mackall: There's a perfect storm to bring immunotherapy into the mainstream of pediatric cancer. New immunotherapy technologies are available, new drugs are coming out that are active against adult cancer, and biotech and pharmaceutical companies are very interested in the opportunities.

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