Children’s Brain Tumor Project Lab Update: Fall 2016

Posted in Research

As many of you probably read about on Facebook, on September 8 we treated the final patient in our Phase I clinical trial of convection-enhanced delivery (CED) for diffuse intrinsic pontine glioma (DIPG). The trial, which had enrolled 27 patients over the past four years, was designed to test the safety of CED as a means of delivering a cancer-fighting drug directly to the site of a DIPG tumor. Four patients received a second infusion, bringing the total number of treatments to 31. This trial has generated a wealth of information, and we have already started publishing academic papers about it, sharing our discoveries with other researchers in the spirit of collaboration that drives this project. Details of the infusion technique, the imaging studies, and other learning that will assist other researchers worldwide have already appeared in academic journals. The “big one,” providing data on the safety of the procedure, will probably take a year or more to prepare for publication. But with no dose-limiting toxicity in any patient, we feel confident that the technique is a safe way to deliver cancer-fighting drugs to a DIPG tumor. The next steps are to identify the most promising drugs to test in future phases of this trial. Fortunately, thanks to our generous donors the legwork on that has already begun. Be sure to read our update on the results of our “summer sprint,” the unprecedented effort that brought a dedicated team of young researchers into the lab in July and August to help us lay the foundation for future trials. These talented young investigators didn’t work only on DIPG, however. The drugs they evaluated, the molecular modifications they tested, and the other innovative lines of research they pursued will be of invaluable help as we continue to forge this path. Thank you all, again, for the continued loyal support that allows us to do this important...

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New Publications From the CBTP, Fall 2016

Posted in Research

“Exploring the role of inflammation in the malignant transformation of low-grade gliomas.” Journal of Neuroimmunology, 2016 Aug 15;297:132-40. Epub 2016 May 25. “A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume.” Journal of Neurosurgery, Pediatrics, 2016 Jul 8:1-8. [Epub ahead of print] “A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas.” AJNR American Journal of Neuroradiology, 2016 Jul;37(7):1367-73. Epub 2016 Mar 3. “Gliomatosis cerebri: A consensus summary report from the First International Gliomatosis cerebri Group Meeting, March 26-27, 2015, Paris, France.” Pediatric Blood Cancer, 2016 Jul 28. [Epub ahead of print] “Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment.” Current Neuropharmacology, 2016 Jun 13. [Epub ahead of print] “Clinical Genomics: Challenges and Opportunities.” Critical Reviews in Eukaryotic Gene Expression, 2016;26(2):97-113. Click on any of the links above to read summaries of these papers on...

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Exciting Results from the ”Summer Sprint”

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Thanks to a number of grants and private donations, in July and August the CBTP lab team was joined by several young researchers working on specific projects to advance the field of pediatric neuro-oncology. This “summer sprint” was an unprecedented effort that produced some excellent results. Umberto Tosi, funded by a POST grant from the Alex’s Lemonade Stand Foundation, worked on a project to improve the measurement of drug delivery to the brain via “theranostic” (therapeutic and diagnostic) agents. The usual method of determining whether a drug has been successfully delivered is to wait for a clinical response, a “wait-and-see” approach that is neither timely nor precise. If researchers could modify a drug to make it fluorescent—and therefore visible on PET or MRI imaging—they would be able to see in real time whether that drug has reached its target. The key is to make delivery of the drug visible and measurable without reducing its effectiveness. Working with collaborators at Weill Cornell Medicine’s Molecular Imaging Innovations Institute (MI3), Umberto tested several modified versions of the drug dasatinib both in vitro (in petri dishes) and in vivo (in animal models). Several of them acquired their new imaging potential while retaining their therapeutic properties, and they will advance to further rounds of testing on several different malignancies. The modification technique was then performed on panobinostat, a drug that has already shown significant promise in the treatment of DIPG. As we had hoped, the modified panobinostat was successfully imaged with PET/CT and its therapeutic properties were not altered. We hope this new compound will allow for a more precise treatment of DIPG. Raymond Chang tested ways to combine drugs to defeat DIPG, which has defense mechanisms that allow it to evade otherwise effective drugs. Research has identified certain molecular signaling pathways that could be promising targets for drug therapy, but the tumor has alternative pathways that allow it to grow despite use of a single drug. Raymond tested several drugs, individually and in combination, on DIPG cell lines grown in our lab and discovered one potent inhibitor of DIPG growth in vitro. After combining that drug with several other classes of drugs, he found a MEK-inhibitor that showed substantial synergistic effects. Raymond will continue his work in the lab, where he is now using xenograft mouse models of DIPG to demonstrate that this drug combination will be more effective in reducing tumors than either drug individually. Raymond’s summer assignment was funded by the American Brain Tumor Association. Emilie George established in vitro cell models of gliomatosis cerebri (GC). Together with the Greenfield lab team, Emilie initiated a drug screening protocol to begin testing chemotherapeutic agents on this newly developed cell model. This project...

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Children’s Brain Tumor Project Lab Update: Spring 2015

Posted in Research, Updates

By Dr. Mark Souweidane and Dr. Jeffrey GreenfieldCo-Directors, Children’s Brain Tumor Project This lab update is more like a chorus of “On the Road Again,” as we have both been traveling so much this spring. As reluctant as we always are to leave our work here, that travel has been invaluable in the sharing of information and the enhancing of our worldwide collaborations. The DIPG Workshop in Barcelona in February brought together experts from all across the United States and Europe, from cities including Amsterdam, Helsinki, and London—not to mention institutions such as the NIH, Duke, Dana Farber, Northwestern, and Weill Cornell. The workshop is made possible through the efforts of the Alicia Pueyo Fund, a family foundation dedicated to finding treatments for brainstem gliomas and encouraging collaboration among researchers worldwide. We are honored to participate alongside other international leaders who are striving to defeat DIPG, and grateful to the dedicated families who are at the forefront of the effort, always refusing to take no for an answer. March meant Paris, for the first-ever International Gliomatosis Cerebri Conference, organized and driven by families affected by GC. That groundbreaking meeting created a framework for important collaborations as we go forward. (Click here to read more about both conferences.) In April, we look forward to the annual meeting of the DIPG Collaborative in Chicago. The 2015 Symposium promises to be filled with new research and development about this tumor, which is one of the prime targets of our research efforts here at the...

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News From Barcelona and Paris

Posted in Research, Updates

In February, Dr. Souweidane attended the Alicia Pueyo Workshop on DIPG in Barcelona, where he presented an update on the use of convection-enhanced delivery (CED) for DIPG to an international audience of scientists, clinicians, and family advocates. As Dr. Souweidane’s clinical trial approaches completion, other groups are highly interested in learning more about CED, as evidenced by the invitations he has received to present this innovative strategy: as a keynote speaker at the University of Alabama Birmingham/Children’s Hospital of Alabama for its annual Pediatric Neuro-oncology Symposium on May 1, at the DIPG Collaborative Symposium in April in Chicago, and as the 2015 E. Bruce Hendrick Visiting Professor at the University of Toronto/Hospital for Sick Children on May 22. In March, an unprecedented constellation of scientists and oncologists met in Paris to discuss the status of diagnosis, treatment, and scientific inquiry into gliomatosis cerebri (GC), a disease so close to many of us at the CBTP. Dr. Greenfield cohosted the two-day gathering, which took place at the Institut Curie. Developments included an agreement that Weill Cornell will host the International GC Registry with back-end analytic support from the DIPG community. The ICB in London and Weill Cornell in New York were also selected as the European and North American sites for sample collection and comprehensive genomic analyses. The panel discussed new scientific projects to focus on and the concept of a GC-specific clinical trial within two years. This cross-continental initiative is truly a remarkable example of the efforts that can result from collaboration and...

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Children’s Brain Tumor Project Lab Update: Fall 2014

Posted in About the CBTP, Research, Updates

By Sheng Li, Ph.D. Ty Louis Campbell Fellow I am so grateful for the opportunity to work with the Children’s Brain Tumor Project as the first Ty Louis Campbell Fellow. I thank Cindy and Lou Campbell and the TLC Foundation for funding this creative position. My passion is bioinformatics and computational biology, both of which play critical roles in decoding tumors such as DIPG, gliomatosis cerebri, and AT/RT—the cancer that claimed Ty’s life two years ago. After receiving a bachelor’s degree in biotechnology from Sun Yat-sen University in Guangzhou, China, I came to Weill Cornell in 2009. I’ve been here for the past five years as a Ph.D. candidate in computational biology, during which time I have published research articles on high-throughput sequencing data analysis for cancer biology in Nature Biotechnology, Nature Genetics, Journal of Clinical Investigation, and Genome Biology. I’ve also been a lecturer in cancer genome data analysis for courses at Weill Cornell Medical College and the Institute of Computational Biomedicine’s EpiWorkshop. I completed my doctoral dissertation on the topic of cancer epigenetic dysregulation, and I’ll be further pursuing that research in this fellowship. The science of epigenetics is relatively new, and it’s emerging rapidly. The term refers to changes in the ways genes are expressed that don’t change the DNA itself. Disruptions in the epigenome are thought to play a fundamental role in how cancer develops, but how those disruptions happen are only just now starting to be understood. Because they occur spontaneously, they cannot be predicted—which is why the rare and inoperable tumors that strike children seem to come from out of the blue. There are no known risk factors, no family history, no warning signs—just a child who is healthy one day and terminally ill the next. For answers, we must comb through a staggering amount of data that can now be produced through sequencing and other studies. Today’s high-throughput sequencing methods are faster and more accurate than they were even just a few years ago, but each tumor sequenced produces an avalanche of data that must be pored over and analyzed by a bioinformatics specialist in order to find answers and draw conclusions—or at least identify new pathways for future studies. I am proud to be playing a role in the Children’s Brain Tumor Project’s multi-pronged research efforts—banking tissue for future study, sequencing tumors from a wide range of patients, interpreting the data produced from sequencing those samples, and then testing new drugs and new delivery methods selected specifically for that individual tumor. The Department of Neurological Surgery is working with the Department of Pathology, the Cancer Center, and the Center for Precision Medicine here at Weill Cornell as well as collaborating with...

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