New Affinity Group Bolsters Understanding of DNA-Protein Interaction

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New Affinity Group Bolsters Understanding of DNA-Protein InteractionNew Affinity Group Bolsters Understanding of DNA-Protein Interaction

Research at Children’s Hospital is organized not only by clinical departments but also by scientific discipline. Extending beyond the traditional academic structure — for example, cardiology or immunology, among many others — the Institute’s Centers of Emphasis and Research Affinity Groups are structured to foster collaboration and innovation.

The affinity groups at the CHOP Research Institute reflect the increasingly interdisciplinary and multidisciplinary nature of many key research questions. This approach aligns with the emerging national consensus that multidisciplinary centers are essential to advancing the nation’s research agenda. One of the most critical areas benefiting from this forward-thinking approach to research is with respect to genomics.

Since the completion of the Human Genome Project, there has been a natural surge in biomedical research aimed at gene discovery. Using genome-wide association studies (GWAS), bioinformatics, and other approaches, this process has focused largely on determining what genes are implicated in specific diseases.

While this process may shed light on what genes are involved in diseases, it has done little to help investigators understand why a gene or genomic region may be involved in a disease or a disease risk.

A new Research Affinity Group at CHOP Research is taking the findings from various types of studies, including GWAS, a step further in order to understand entire networks underpinning disease susceptibility.

At the heart of the DNA-Protein Interaction Research Affinity Group is the analysis of data derived from chromatin immunoprecipitation coupled with high-throughput sequencing. More commonly referred to as ChIP-seq, the technique is used to look at how proteins like transcription factors interact with DNA, and to find the regions of the genome these transcription factors occupy to control gene expression.

The DNA-Protein Interaction research affinity group, co-led by Struan Grant, PhD, of the Department of Pediatrics and Genetics, and Andrew Wells, PhD, of the Department of Pathology, deals with the processing and analyses of ChIP-seq and related data to gain insight into disease networks, identify vulnerabilities in given networks, and look for points amenable to therapeutic intervention.

“The new affinity group is a forum for investigators with diverse backgrounds and expertise to learn the downstream effect of transcription factors and related DNA binding proteins,” says Dr. Grant. “We can now work to analyze and translate the numerous findings made from GWAS and elsewhere — a natural step in discovering not only what causes disease but why.”

Also relevant to the goal of the affinity group is leveraging the data from the public research consortium ENCODE — the Encyclopedia Of DNA Elements — to better understand and integrate genome-wide data sets generated by investigators at CHOP. Launched by the National Human Genome Research Institute nearly a decade ago, the ENCODE project aims to ultimately identify all functional elements in the human genome sequence.

“The sequencing of genomic information is not the bottleneck — it’s the analysis,” says Dr. Wells. “The DNA-Protein Interaction affinity group creates a community that can benefit from what we can learn about disease networks through ChIP-seq and related techniques, and then develop a pipeline to find novel ways to understand and target those diseases.

Exploring the Genetic Landscape of Children’s Brain Tumors

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Exploring the Genetic Landscape of Children's Brain TumorsExploring the Genetic Landscape of Children's Brain Tumors

Though enormous advances have been made against childhood cancers in recent years, pediatric brain tumors remain devastating: childhood brain tumors are the second leading cause of cancer-related death in children. There are many different types of pediatric brain tumors, and their location — in the brainstem, cerebellum, cerebrum, or spinal cord — often means that children with brain tumors face extremely challenging treatment regimens.

For example, the treatment for medulloblastoma, the most common form of malignant brain tumor in children, can be onerous. Typically, children with medulloblastoma must first undergo surgery, which is then followed by chemotherapy and radiation. And cancer treatments can cause a range of debilitating side effects, including heart and lung abnormalities, reproductive issues, cognitive and developmental challenges, and in some cases secondary tumors.

Despite these sorts of challenges, only a fraction of the National Cancer Institute’s (NCI) budget is devoted to supporting childhood cancer research and pediatric brain tumor research. For example, in 2011 the NCI devoted $195.5 million to pediatric cancer research, out of a total budget of more than $5.058 billion — slightly less than 4 percent. Clearly then, in an era of decreased federal funding for scientific research, other approaches are needed to improve the health of children with brain tumors. One such approach is the Childhood Brain Tumor Tissue Consortium (CBTTC).

The CBTTC is multi-institutional, collaborative research organization dedicated to the collection, annotation, and analysis of children’s brain tumors, with the ultimate goal of improving outcomes for children with brain tumors. The CBTTC is comprised of The Children’s Hospital of Philadelphia, the Children’s Hospital of Pittsburgh of UPMC, Seattle Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago. The consortium’s operations center is housed at Children’s Hospital.

Tom Curran, PhD, FRS, deputy science director of the Children’s Hospital of Philadelphia Research Institute, Peter C. Phillips, MD, director of CHOP’s Pediatric Neuro-Oncology Program, Phillip (Jay) Storm, MD, incoming CHOP Neurosurgery Division Head, and Adam Resnick, PhD, Assistant Professor of Neurosurgery, lead Children’s Hospital’s involvement in the CBTTC. The consortium was initially set up with the support of the Childhood Brain Tumor Foundation (CBTF), who then partnered with the International Licensing Industry Merchandiser’s Association (LIMA) to further develop the consortium’s infrastructure. Both the CBTF and LIMA continue to lend key support to the CBTTC’s efforts.

“Children with brain tumors deserve the very best that science has to offer,” Dr. Curran said, but unfortunately “many groups struggle to obtain enough specimens for their studies. Therefore, we decided several years ago that the best way to make progress was to share all materials, all data and, especially, all ideas in pursuit of better treatments.”

Consortium member institutions are currently engaged in several research projects. Three projects are investigations of specific types of brain tumors — craniopharyngiomas, diffuse fibrillary astrocytomas, and gangliogliomas — while a fourth project is focused on better understanding pediatric and adult gliomas. Much of the consortium’s work is reliant on genomic sequencing, which is performed at Children’s Hospital.

In addition to collaborating on research projects, consortium members freely share biospecimens, data, and ideas on how to apply the latest technologies to pediatric brain tumor research. Notably, in the fall of 2013 the CBTTC biorepository was launched. The biorepository has the ability to receive specimens for member institutions, and can bank cerebral spinal fluid, DNA, RNA, and tissue samples. And in fiscal 2013, the CBTTC Data Specimen and Inventory portal — an online system built on a platform designed by Children’s Hospital’s Center for Biomedical Informatics — was made available. The new data platform allows researchers around the world free access to brain tumor data 24 hours a day.

CBTTC-associated researchers have also been working outside the laboratory to raise awareness of childhood brain tumors. Recently, Children’s Hospital investigators traveled to Capitol Hill to report on the important brain tumor research being done at CHOP as part of the CBTTC. Dr. Resnick, along with Kristen and Rich Gillette of the Kortney Rose Foundation, met with staffers from the offices of New Jersey Sens. Bob Menendez and Jeff Chiesa, as well as Rep. Frank Pallone.

With the ongoing support of the CBTF and LIMA, the CBTTC has made great strides toward its goal of increasing worldwide brain tumor-related research collaboration. Through the integration of a state-of-the-art biorepository of tissue samples, informatics advancements, and by bringing together experts from around the world, the consortium is positioned for long-term growth and sustainability. By laying the foundation for new treatments, the CBTTC is working to inform therapeutic decisions and improve outcomes for children with brain tumors.

To learn more about the Childhood Brain Tumor Tissue Consortium, visit the consortium’s website.

Spreading Knowledge: CHOP Research Hosts Major Genomic, Cancer Conferences

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Spreading Knowledge: CHOP Research Hosts Major Genomic, Cancer ConferencesSpreading Knowledge: CHOP Research Hosts Major Genomic, Cancer Conferences

Making discoveries, publishing results, and striving to translate research findings to clinical care are major aspects of the research endeavor at Children’s Hospital. But the efforts don’t stop there.

Sharing scientific knowledge and spurring meaningful conversations with colleagues both inside and outside of the CHOP Research community about trends in research, future needs, and new approaches, all contribute to the collective scientific knowledge and help advance research.

In another sign of its leadership in biomedical research and care, in FY13 CHOP Research hosted two meetings that brought together world-class gatherings of researchers and clinicians.

Both the genomics-focused ICG Americas 2012 conference and the Center for Childhood Cancer Research’s inaugural pediatric cancer symposium featured pioneering investigators from both inside and outside the Research Institute, discussing the groundbreaking work of today that will lead to the cures of tomorrow.

Held last September, the ICG Americas 2012 conference was the first international meeting on genomics to be held in the United States, and was hosted jointly by international genomics institute BGI and Children’s Hospital. More than 350 genomics researchers, industry executives, and policymakers attended.

“I think that everybody knows that we’re truly on the dawn of a revolution in genomics, in medicine, and in healthcare,” said Steven M. Altschuler, MD, CHOP chief executive officer, in his welcoming remarks. Genomic technology and research “has the potential to radically change the way that we think about the delivery of healthcare,” Dr. Altschuler said.

Among the more than 50 speakers at the ICG Americas 2012 conference were CHOP’s own Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, and Douglas Wallace, PhD, director of the Center of Mitochondrial and Epigenomic Medicine. Eric Green, MD, PhD, director the National Human Genome Research Institute, and Huanming Wang, PhD, chairman of BGI, also presented.

“No doubt it’s a revolution … no doubt it’s an opportunity,” Dr. Wang said of the promise offered by genomic medicine, after noting that 2013 marks the tenth anniversary of the mapping of the human genome and the 60th anniversary of the publication of DNA’s double helix structure.

Dr. Hakonarson’s talk highlighted his work with a fasoracetam, a drug that was originally developed to treat Alzheimer’s disease but, after being put through clinical trials, was shelved for efficacy reasons. Dr. Hakonarson and his team are now investigating whether the drug can be used to treat attention deficit hyperactivity disorder, a project he called a “representation of what genomics is offering.” Using genomics to determine new indications for available products can help speed therapies to market, Dr. Hakonarson noted.

Genomic medicine allows researchers “to identify a subset of patients who have mutations in certain gene pathways and networks that disturb the networks and, when you are lucky and a drug already exists that has already been proven safe, the ability to take a shortcut and fast-track a clinical trial and subsequently get a drug out is obviously significantly enriched,” Dr. Hakonarson noted.

A few weeks later the Center for Childhood Cancer Research (CCCR) held its inaugural symposium on pediatric cancer research. The meeting focused on translational research, or “how the work is going to impact patients in real time,” said John Maris, MD, director of the CCCR.

The day included presentations from pioneering cancer researchers and innovators, including Columbia University’s Adolfo Ferrando, MD, PhD; Kevin Shannon, MD, from the University of California San Francisco; and the Broad Institute and Harvard Medical School’s Matthew Meyerson, MD, PhD. The symposium was made possible with support from Alex’s Lemonade Stand Foundation.

In his opening remarks, Philip R. Johnson, MD, chief scientific officer of the CHOP Research Institute and executive vice president, noted that while he has at times struggled to translate what constitutes translational research into “understandable stories,” the work done by the oncology group always made his job easier. People “get it immediately, they understand that the science impacts the care and the care impacts the science,” Dr. Johnson said.

A number of the day’s presentations focused on using the highly specific targeting offered by genomics to treat cancer, with the CCCR’s Yael Mossé, MD, giving a talk on her work treating neuroblastoma in patients who express the anaplastic lymphoma kinase (ALK) gene. Dr. Mossé’s investigation of crizotinib, a drug originally developed to treat lung cancer in adult patients who express ALK, sparked a frenzy of media attention in the spring after Dr. Mossé and her team found complete responses in a number of patients involved in a phase 1 trial.

Though the “inhibition of mutated ALK is complex and remains a therapeutic challenge,” it is her patients who “really inspire me every day,” Dr. Mossé said.