NEW YORK – With support from the National Institutes of Health, investigators at the Children's Hospital of Philadelphia have begun a new effort to develop a comprehensive clinical and genomic dataset to improve precision medicine for childhood brain tumors.
Led by CHOP's Center for Data-Driven Discovery in Biomedicine (D3b), the program is sequencing samples from thousands of childhood brain cancer patients and their families, collating this data with clinical phenotypic records, and developing tools to make the resulting platform widely available for research and immediate clinical translation.
Adam Resnick, co-director of D3b, said this week that hoped-for outcomes include both discovery of new drug targets and the potential to repurpose existing precision therapies — drugs that might work in pediatric brain tumors but haven't been noted as options before because of a lack of data.
"This dataset is poised to provide a canvas of information against which the next patient who comes through CHOP's or any hospital door can be positioned against and interpreted," Resnick said. "Up until now, each patient was largely in isolation because there was no information against which you can say 'show me 10 other patients across the globe that have the same mutational landscape or the same phenotypes as this patient.' So now, for the first time, they'll be this public resource that will support decision making at the clinical interface."
Although childhood brain tumors are rare, with an estimated 4,600 new cases in the US expected this year, according to CHOP, they cause a large proportion of disease-related deaths in those aged 19 and under. And despite decades of research, several pediatric brain tumor types remain largely incurable.
The NIH support for the D3b program takes an interesting form. Rather than providing a monetary award, the NIH is connecting the program with access to sequencing resources at the Broad Institute.
The multi-institution Children's Brain Tumor Network, for which Resnick serves as co-chair, is aiming to collect whole-genome sequences for what will be the largest clinically annotated pediatric brain tumor cohort study to date, including over 4,500 samples collected by D3b.
In addition to being the coordinating center for the CBTN, D3b is also leading the development of the data resource center for the NIH common fund-supported Gabriella Miller Kids First Pediatric Research Program.
Resnick said that the various arms and initiatives will hopefully allow the group to create ways for the fruits of their core data collection effort to have broad impact.
"We recognize that, as great as CHOP is, the discovery process also takes a community-based effort, and we want to ensure that this happens as rapidly as possible, so not only are we going to be generating these data sets … but we are also going to be supporting the analysis as [an] open science initiative," he said.
Resnick said he and his team recognize that the translation of data into clinical management is not something that is easily democratized. "Doctors don't have time to essentially reanalyze large-scale genomic data as they're treating patients, so one key to our efforts has been the development of portals that support the rapid query of already processed and analyzed data."
Resnick said the program is a "pan-brain tumor effort" at its core, although there are disease-specific working groups focused on specific tumor types.
Examples of particularly pressing targets, he said, include diffuse intrinsic pontine glioma. "Currently when a child is diagnosed with that tumor, nearly universally, they succumb to the disease in less than a year. And that's in part because we don't have a therapeutic intervention that's specific for that tumor type that fully addresses the biology of that tumor."
"Our hope is to enrich those data resources such that the drug-development efforts are targeted for those tumors and their biology," Resnick said.
Another way the group is hoping the data will be informative is in tumor types where there has been some prior genomic discovery, but on a much more targeted scale.
"For tumor types like low-grade gliomas there's been some data generated in the past ... genomic mutations ... some alterations, but it isn't a complete view of the genome, for example. That's important because it turns out that we may have two patients with the exact same mutation, but they have different outcomes and different responses to drugs in ways that we don't understand," Resnick said.
"Our hope is that by enriching and creating a more comprehensive view of the biology, as well as the clinical, phenotypic, and imaging data, we can begin to tease that apart and be able to … predict that you're not going to respond versus a patient that is going to respond," he added.
According to CHOP, the first year of the effort will be taken up with preparing and shipping samples for sequencing at the Broad Institute. Next, the group will work to harmonize the resulting clinical and genomic data so that it can be accessed and analyzed by Kids First participants.
Resnick added that one of the most important unique features of the effort is a commitment among academic institutions to share and make public their findings as rapidly as possible.
"That is still not the norm in most academic practices … [but] I mentioned, for example, that some of these tumor types have a median survival of between nine and 12 months, so you can imagine that any data embargo of even six months is a significant portion of a child's potential survival time. So one of the narratives for us is also that there is a leadership role that the pediatric community is taking in data empowerment that's probably unparalleled in adult-based efforts," he said.