Families struggling to find a diagnosis can turn to a team of super sleuths from Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania who are ready to unravel these perplexing diseases. A core group of expert clinician-scientists will leverage their collective brainpower to tackle these tough cases and consult with ad hoc members — “superstars” of their specialties — when needed to shed light on each patient’s condition from multidisciplinary perspectives.

The two institutions received $2.5 million in research grants from the National Institutes of Health as a newly designated Undiagnosed Diseases Network (UDN) site. Kathleen Sullivan, MD, PhD, chief of the Division of Allergy Immunology at CHOP and Reed Pyeritz, MD, PhD, the William Smilow Professor of Medicine and professor of Genetics at Penn, are co-directors for the joint CHOP/Penn site.

The UDN research study was developed to improve and accelerate the diagnosis of conditions that are rarely seen, have not previously been described, or are unrecognized forms of more common diseases. Since its launch in 2015, the UDN has diagnosed more than 200 cases that had long confounded the medical community, yet many more remain unexplained.

Arriving at an accurate diagnosis is like finding a key to that could unlock treatment possibilities; however, the National Human Genome Institute reports that about 95 percent of rare disorders do not even have one treatment approved by the Food and Drug Administration. If an effective treatment doesn’t already exist, CHOP Research Institute has an ideal bench-to-bedside infrastructure to expedite the UDN team’s ability to successfully engage with basic science researchers who are eager to participate in projects that eventually could change children’s lives.

“It’s humbling and exciting that we’re at the forefront of learning about different types of diseases and what the diseases look like in different patients,” Dr. Sullivan said. “I hope we can help in some way all of the families who come to us through the network and are desperate for the right answer.”

New grants awarded by the National Cancer Institute Moonshot Initiative through a multi-institutional, collaborative group — the Pediatric Immunotherapy Discovery and Development Network (PI-DDN) — aim to fundamentally change our understanding of how to harness the power of the immune system to treat childhood cancers.

“Cancer is sinister and, generally, when you think you have a leg up on cancer, it figures out a way to outsmart you,” said John M. Maris, MD, pediatric oncologist and Giulio D’Angio Chair in Neuroblastoma Research at Children’s Hospital of Philadelphia, whose research team received funding to lead a pediatric immuno-oncology Center for Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers. “We are trying to develop breakthrough therapies to fundamentally change the paradigm of how we treat childhood cancers.”

The Center is a collaboration led out of CHOP with Stanford University, the University of Wisconsin, Texas Children’s Hospital, and the British Columbia Cancer Agency in Vancouver.

A key part of this success, Dr. Maris said, will be to discover immunotherapeutic strategies for childhood cancer that not only improve cure rates, but also are less toxic than current therapies.

The Center includes three highly integrated multicomponent projects that will occur in parallel and inform each other.

In project one by the Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers team, the researchers aim to discover lineage-specific cell surface molecules that have project-defined optimal attributes for synthetic immunotherapeutic-based targeting. They will use their findings to create and credential new therapeutics based upon preclinical efficacy in high-risk childhood cancer models.

The second project will focus on major mechanisms of immunotherapy resistance by developing approaches to circumvent the fundamental issues of intra- and inter-tumoral heterogeneity and T cell dysfunction due to both intrinsic and extrinsic factors.

Project three will probe the major difference between pediatric and many adult malignancies: Pediatric cancers typically elicit little adaptive immunity. Scientists’ goal will be to develop approaches to enhance adaptive immune responses against pediatric cancer-specific antigenic targets.

With the underpinnings of state-of-the-art technology and interdisciplinary teamwork, the Center is poised to extend the early accomplishments of CD19-directed immunotherapies in a limited number of highly refractory cases of pediatric leukemia and neuroblastoma. They will use these insights to improve scientists’ understanding of the fundamental mechanisms in other high-risk or difficult-to-treat childhood cancer phenotypes, including how these malignancies evolve to evade the immune system and resist modern therapies. Beyond the stated goals of the grant, researchers are working to identify opportunities for collaboration.

“The idea is for this to be greater than individual projects, that there will be a network of expertise with the mark of the Moonshot behind it along with some significant resources to help us with our research goals,” Dr. Maris said.

Two cutting-edge, cooperative biomedical research projects — the Center for Pediatric Tumor Cell Atlas and the Pediatric Cell Atlas (PCA) — are exploring the potential of single cell technology to zero in on pathogenesis of cancer and other diseases.

Novel technologies have become available in recent years that combine next-generation sequencing and massively parallel processing, such as RNA sequencing, of single cells. These single cell studies, said Deanne Taylor, PhD, director of Bioinformatics in the Department of Biomedical and Health Informatics at Children’s Hospital of Philadelphia and a research assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, open up a high-definition view of cell physiology and functioning that will expand scientific knowledge of health and disease — particularly during the dynamic childhood period, when growth and development are underway.

The PCA will compile age-matched trajectories of tissue and organ development in healthy children, referencing key data patterns in cell differentiation and cell signaling. Those trajectories will offer a standard for researchers to better understand when and how childhood illnesses diverge from those patterns, because of genetic influences, environmental factors, or both. Enabled by dramatic advances in single-cell technology, the PCA will offer an unprecedented window into the unique biology of children by benchmarking healthy and abnormal tissues at the molecular level.

“Ultimately, researchers would leverage knowledge from single-cell data into a deeper understanding of organ development and function, to better inform precision treatments to advance children’s health,” said Dr. Taylor, who is co-author of an open-access perspective article on the PCA in the journal Developmental Cell.

The PCA is a cornerstone of the Human Cell Atlas (HCA), a global effort into understanding human single-cell biology. As part of the broader international consortium represented in the HCA, the PCA will share data among members and with other researchers worldwide. It will also store data in the HCA’s repository with associated biobanking and data repositories in different centers available to biological researchers. As the PCA moves forward, it will develop its overall organization, protocols, data systems, and multiple projects, including pilot studies of specific organs and diseases.

In addition, the PCA will compare atlas data from healthy tissues with data from diseased tissue, such as those generated by the Center for Pediatric Tumor Atlas. Awarded a five-year research grant totaling $12.5 million, Kai Tan, PhD, an investigator in the Center for Childhood Cancer Research (CCCR) at CHOP, and co-principal investigator Stephen Hunger, MD, chief of the Division of Oncology and director of the CCCR, created the Center as part of a 10-center national consortium.

Drs. Tan and Hunger will work closely with other key investigators in the CCCR at CHOP including Kristina Cole, MD, PhD; Kathrin Bernt, MD; David Barrett, MD, PhD; John Maris, MD; Kristopher Bosse, MD; and Sharon Diskin, PhD. Additional off-site key investigators are Hao Wu, PhD, assistant professor of genetics, and Nancy Zhang, associate professor of statistics, both at University of Pennsylvania, and Kun Zhang, PhD, professor of bioengineering at University of California at San Diego.

Their project is under the umbrella of the larger Moonshot Human Tumor Atlas Network (HTAN) that aims to generate atlases of a diverse cancer patient population and high-risk cancers. The CHOP team is the only pediatric cancer group recipient on account of its world-class pediatric cancer researchers, large volume of patients, and unique ability to acquire biosamples of pediatric cancer.

HTAN will generate a large volume of genomic data, imaging data, and clinical data with a three-pronged goal: an easily searchable, publicly available database; research community access to the computational tools utilized in the project; and access to biospecimens including tissue sections, viably frozen specimens, and patient-derived xenograft models.

“I’m very excited about the kind of promise that can deliver, and that excitement is shared by all the researchers,” Dr. Tan said. “Single cell technologies is revolutionizing biomedical research, not only cancer but other diseases as well.”

As a single-cell zygote proliferates into a 37 trillion-cell being, something happens in the course of its development — a dysfunction, a deviance, a DNA-driven decision — that underpins not just the development of life-changing birth defects, but a potential vulnerability to childhood cancer as well.

Adam Resnick, PhD, co-founder and co-director of the Center for Data-Driven Discovery and Biomedicine (D³b) at Children’s Hospital of Philadelphia, thinks that to unravel the inextricable link between childhood cancer and other rare conditions, we must visualize pediatric cancer as a process. A unique and pioneering endeavor launched in September 2018, fueled by technology and funded by the National Institutes of Health (NIH) Common Fund, is providing investigators with a powerful tool for piecing together the science behind Dr. Resnick’s vision: a comprehensive discovery platform for data — and volumes of it.

The Gabriella Miller Kids First Data Resource Center (Kids First DRC) is a multi-institute collaboration that aims to advance our knowledge of cancer and birth defects through large-scale sharing of genomic, phenotypic, and clinical information. Investigators, clinicians, data scientists, and patients are working together to continuously improve the Kids First DRC’s chief outward-facing tool: a centralized, cloud-based database and discovery portal containing well-curated clinical and genetic sequence data.

The data contained within the Kids First DRC is being generated from tens of thousands of sequenced biosamples to determine if mutations or genetic changes exist for each disease type. Users worldwide can access the genetic disease data at one central location, share their findings, or collaborate in real time.

The Kids First DRC is part of the broader Gabriella Miller Kids First Pediatric Research Program, launched in 2015 by the NIH Common Fund to help researchers better understand the role of genetics in childhood cancer and structural birth defects, and the genetic pathways underlying these conditions. The Kids First DRC combines efforts between CHOP, CHU Sainte-Justine Research Center, the Ontario Institute for Cancer Research, the University of Chicago, Children’s National Health System, Oregon Health and Science University, and Seven Bridges.

In addition, the Kids First DRC supports collaborations within CHOP, including the partnership between the Craniofacial Program and the D³b Center. Although statistics show that children with a cleft palate or birth defect of the central nervous system are two to four times more likely to have a cancer, scientists have yet to understand the potential genetic pathways and links underlying both conditions.

“By learning more about brain tumors, we may help ourselves to learn more about other congenital anomalies,” said Jesse Taylor, MD, attending surgeon in the Division of Plastic and Reconstructive Surgery at CHOP and a co-investigator of the Kids First DRC. “And by learning about the congenital anomalies like craniosynostosis, we may learn more about how to treat brain tumors.”

The Pediatric Preclinical Testing Consortium (PPTC) announced their new pediatric cancer model datasets are now available to any qualified academic petitioner, putting information about both patients’ genetic data and their response to various drugs at scientists’ fingertips. This is the first time that an academic consortium has teamed up to generate data to guide drug development.

With the release of more than 244 genomic tumor models spanning 27 different types of childhood cancer, researchers may now have the ability to skip lengthy preclinical work in their development of novel treatments. The traditional process was to test a drug, learn that some tumors responded and some didn’t, and then researchers would need to go through the exercise of trying to figure out why. Finding that “why” could take months or even years.

“Now, the explanation may be right in front of us because it was either the exact hypothesis we were testing there that had the mutation or not, or even if our hypothesis was wrong, we have this enormous amount of data at our disposal to ask: Why did some respond, and why did some not?” said John M. Maris, MD, oncologist at Children’s Hospital of Philadelphia Cancer Center and principal investigator of the PPTC’s CHOP site. “I think that we’ve streamlined significantly.”

With funding from Alex’s Lemonade Stand Foundation, the project will enable more precise clinical trials by not only allowing scientists to draw on previous analyses (so as to identify the most impactful drugs to take to clinical trials and avoid repeating failed experiments), but also by providing researchers with a wealth of data on genetic targets rather than broad disease types.

“This really is about moving toward treating pediatric cancer not as diseases, but as molecular entities,” Dr. Maris said. “Five patients who have neuroblastoma and their tumors look identical under the microscope, may actually be genetically very distinct.”

The PPTC is a National Cancer Institute-funded academic collaboration between CHOP, Greehey Children’s Cancer Research Institute in San Antonio, Ann & Robert H. Lurie Children’s Hospital of Chicago, MD Anderson Cancer Center in Houston, the Children’s Cancer Institute in Sydney, and the Research Triangle International coordinating center in Research Triangle Park, North Carolina.

As the only release of childhood cancer data where multiple types of different cancers are all analyzed together, the PPTC offers a unique resource of genetic data as well as response data to different drugs.

“Making that available broadly will allow other researchers to either not repeat experiments that are doomed to fail or extend experiments that look very interesting,” Dr. Maris said.

The Penn Center for Nutritional Science and Medicine (PenNSAM) brings researchers from the University of Pennsylvania and Children’s Hospital of Philadelphia together to investigate nutritional biology in the prevention and treatment of disease.

Under the direction of Gary Wu, MD, academic investigator in childhood obesity research at CHOP and a member of the Division of Gastroenterology at Penn, PenNSAM will focus on integrating human clinical metadata, traditional dietary assessments, and standard nutritional biomarkers with data generated by high-throughput molecular profiling technologies and analyzed through advanced biostatistical and computational algorithms. These capabilities enable the PenNSAM team to employ a holistic approach using genomics, proteomics, and metabolomics, combined with immune profiling, to further understanding of the impact of nutrition on human health.

Drawing on the knowledge of Penn and CHOP experts in disciplines ranging from psychiatry, neuroscience, and medicine, to immunology, biochemistry, and bioinformatics, PenNSAM is a uniquely resourced center for the advanced study of human nutrition. This multidisciplinary approach also bridges the divide between human subject and wet bench research, enabling investigators to develop model systems designed to more precisely identify and characterize molecular mechanisms that drive the human response to diet and nutrition.

Advanced analytic technologies available through the support of the Human Subject Research Core, Biobanking Core, Computation and Biostatistics Core, Quantitative Proteomics Resource Core (QPRC), PennCHOP Microbiome Program, and the Human Immunology Core at Penn allow a systems approach to human nutritional biology.

Projects currently under development at PenNSAM include studies focused on the impact of diet on brain function through the consumption of a ketogenic diet, the characterization of molecular markers that distinguish a healthy Mediterranean diet from an unhealthy “convenience diet,” and a study focused pancreatic insufficiency.

“The close collaborative relationship between CHOP and Penn will facilitate the implementation of projects such as the ketogenic diet study, where studies will be performed at both institutions,” Dr. Wu noted.

PenNSAM researchers envision their holistic approach will lead to reducing the risk for disease by identifying new biomarkers that predict human responses to diet and nutrition, optimizing currently available nutritional interventions for hospitalized patients, and developing novel diet-based interventions to treat disease.