Children’s Brain Tumor Project Lab Update: Spring 2013

Posted in About the CBTP, Research, Updates

By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project One of the most important — and challenging — aspects of working with a disease like gliomatosis cerebri is access to tissue samples. The best way for us to study this tumor is by seeing, testing, and studying many different examples of it, and finding out as much as we can about the young patients diagnosed with it. We believe that’s the key to personalized medicine: Exploring what these tumors, and these patients, have in common, and how they’re different, will help us understand how GC works and how we can defeat it. That’s no easy task — there are only a handful of individuals each year diagnosed with gliomatosis cerebri, so the universe starts out as a small one. If the patient happens to live in a major urban area, with access to a comprehensive medical center, odds are that the surgeons there know about the Children’s Brain Tumor Project and will alert us to the case. In smaller towns and cities across the United States, though, a patient will often be seen and treated first at a local hospital, and we won’t find out about the diagnosis — at least not right away. That’s one of the most critical pieces — timing is everything when it comes to tissue samples. We’re grateful for the number of samples we’ve already received from our partners, but too often these samples are taken during an autopsy, after the tumor has won the battle. Those samples bear the scars of that battle — the tumor has been irradiated or subject to chemotherapy, which changes its molecular makeup. Our lab can learn a lot from these samples, but we could learn so much more if we had access to tumor tissue taken during the original biopsy, before the tumor has been affected by treatments. The challenge is not only one of spreading the word, but of putting the infrastructure in place to retrieve those samples. Imagine what’s entailed in this: First, the medical and surgical teams at a hospital have to know we even exist and need the samples. Then a frightened and overwhelmed patient and family have to learn about us and our work, and give their consent to donate samples. Finally, the sample has to be taken during a biopsy and then shipped to us overnight in a freezer package so it can be received here and stored safely in our lab for study. You can imagine how it would be easy to overlook this entire process in a small hospital, with a medical team that has probably never seen a single case of gliomatosis cerebri before. There’s more to...

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Breaking News From Rockefeller University: Spring 2013

Posted in About the CBTP, Research, Updates

By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project In the last issue of this newsletter, I told you about Dr. David Allis, my colleague across the street at Rockefeller University, and how his basic science research on histones had suddenly emerged as an important element in pediatric brain tumors. I’m thrilled to be working with Dr. Allis on this important research. As I write this issue, a brand-new paper by Peter Lewis has just been published confirming some of our best hopes. Dr. Lewis is a post-doc researcher who works with Dr. Allis, and he was intrigued by the research that linked the H3 histone mutation with the pediatric brain cancer called DIPG. That’s big news in itself, since histone mutations had never before been linked to a specific disease. But Dr. Lewis dug further into the data and made another remarkable finding. A single mutated amino acid on the histone can prevent the process of methylation — the process that “silences” the genes that may make cancer grow. Without that methylation there is no silencing, and without the silencing the gene becomes activated and a tumor can grow. As many as 17 percent of DIPG tumors may be caused by this one tiny aberration in one amino acid. When we find out how to turn methylation on in these cases, we just may have a new way to fight DIPG in those children with this mutation. I’m thrilled by these findings, since they support my belief that the answer to these rare tumors lies in personalized medicine. If we know how to turn on methylation and we can identify those kids whose DIPG is caused by this mutation, we have hope for those children. When we discover the five or ten or more other reasons a tumor can grow, we can develop strategies specific to those tumors as well. Cancer is not one-size-fits-all, and the cures won’t be, either. The findings were published in the April 1 issue of Science Daily. You can read the full article online at sciencedaily.com: “Mechanism of Mutant Histone Protein in Childhood Brain Cancer...

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Summer Research Project Aims to Unlock One of the Secrets of Gliomatosis Cerebri: Spring 2013

Posted in About the CBTP, Research, Updates

Emma D. Vartanian, a medical student at Weill Cornell Medical College, has been awarded a prestigious Summer Fellowship from the Saint Baldrick’s Foundation to work in Dr. Greenfield’s research lab this year. Emma will be dedicated to an exciting project focused exclusively on gliomas. For this research project, Emma will investigate what causes a major difference between low-grade and high-grade gliomas. Low-grade gliomas grow slowly, and individuals diagnosed with these tumors can live for decades. But high-grade lesions are extremely aggressive, and their rapid proliferation means that a patient usually survives less than two years from diagnosis. If we can learn more about how and why these tumors grow so fast, we may be able to find ways to slow them down and make them behave more like their low-grade cousins. That’s not a cure — but if there’s a way to turn a relentless and fatal tumor into a chronic condition, that would be an amazing first step. We already know one reason that high-grade gliomas can grow quickly is because they develop an almost boundless blood supply. A vast network of new blood vessels form at the tumor site in a process called neovascularization, fed by signals from the bone marrow and allowing the tumor to double and redouble in size. This summer’s project aims to test ways to block those signals and prevent neovascularization. Under Dr. Greenfield’s guidance, Emma will use mouse models to study the effects of an inhibitor drug on the progression of gliomas. Using special stains to track which types of cells are mobilized as the tumor grows, and comparing disease progression in treated versus untreated mice, Emma hopes to be able to show that the bone marrow is indeed “recruiting” the cells that drive those new blood vessels to form, and that using inhibitor drugs can successfully delay disease progression by impeding this process. We’re delighted to have Emma on board for such an innovative laboratory project, and we’re grateful to the St. Baldrick’s Foundation for their ongoing support for childhood cancer...

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Children’s Brain Tumor Project Lab Update: February 2013

Posted in About the CBTP, Research, Updates

By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project In our last newsletter, I told you about a new partnership between the Children’s Brain Tumor project and my colleague Dr. David Allis over at the Rockefeller University. This month I’m delighted to announce that the project we’re working on together has just received a two-year, million-dollar grant from the Starr Cancer Consortium. That grant assures that Dr. Allis and our inter-institutional team from Weill Cornell and Memorial Sloan-Kettering can proceed on our histone project, while the Children’s Brain Tumor Project continues on our path of exploring personalized medicine and alternative delivery. The Starr Cancer Consortium is a collaboration among the Broad Institute of MIT and Harvard, Cold Spring Harbor Laboratory, Memorial Sloan-Kettering, the Rockefeller University, and Weill Cornell. Its mission is to fund innovative cancer research projects that can help connect laboratory discoveries to clinical applications. The consortium’s emphasis on inter-institutional projects means that grant recipients collaborate and don’t compete with each other. We at Elizabeth’s Hope and the Children’s Brain Tumor Project couldn’t possibly be better aligned with those goals and principles. The project that received the grant is the one I mentioned last fall: “Elucidating Mechanisms of Histone H3.3 Mutants-Mediated Oncogenesis in Pediatric Brain Cancers.” This is Dr. Allis’s lifelong research work, now with a real-life application. This study, which is able to proceed because of the grant, will investigate how histone H3.3 mutations can lead to the development of gliomas in children and adolescents, with a goal of identifying novel therapeutic strategies. The other investigators on the project with Dr. Allis and me are Dr. Cameron Brennan, Dr. Yu Chen, Dr. Ping Chi, and Dr. Viviane Tabar, all from Memorial Sloan-Kettering. I couldn’t be more excited about working with such a world-class team on such a critically important project. Our momentum is growing, and the generous donors who fund the work of Elizabeth’s Hope have a lot to do with that. My colleague Dr. Mark Souweidane continues his groundbreaking clinical trial using convection-enhanced delivery to bypass the blood-brain barrier in patients with DIPG. My own lab continues to work on sequencing tumors and building our tissue bank so that we can amass more and more data on more and more tumors. Now, with Dr. Allis’s project funded, we are poised for a truly exciting journey over the next few years. I remain deeply grateful, and humbled, by your amazing generosity and commitment to this...

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Children’s Brain Tumor Project Lab Update: Fall 2012

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By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project It has always fascinated me the way seemingly unrelated strands of information can suddenly come together with a resounding bang – one plus one can suddenly equal so much more than two if the strands are the right ones. In this age of instant global communication, the work of researchers on opposite sides of the globe can unexpectedly collide and produce remarkable results. That amazing confluence of events happened just recently, as new discoveries in how genetic mutations can cause cancer suddenly meshed with a lifetime of research by a basic science lab. C. David Allis, Ph.D., the head of the Laboratory of Chromatin Biology and Epigenetics at Rockefeller University, has spent the last 25 years doing basic scientific research on the DNA-histone protein complex called chromatin — his lab has pursued a better understanding of the science underlying the science of DNA folding and unfolding. Histones are the on/off switches that control which genes are active in any given cell, so knowing how to turn a gene off could theoretically head off certain diseases, but Dr. Allis’s work has not been connected to any disease-specific research. It’s basic science, focused on a specific histone called H3.3 — pretty esoteric stuff. That is, until it turned out that H3.3 mutations are significantly associated with pancreatic neuroendocrine tumors (PanNETs), raising the possibility that Dr. Allis’s lab might hold a new key to those cancers. And now the real news: H3.3 mutations are also found in pediatric gliomas. And Dr. Allis is not on the other side of the globe from where I’m doing the work of Elizabeth’s Hope — he’s right across the street from me here in New York. So today I’m ecstatic to announce a new collaboration between Dr. Allis’s lab and the Elizabeth’s Hope project. We’re going to dig a lot deeper into H3.3 to find out just why the mutation causes gliomas — including gliomatosis cerebri — to happen. We’re evaluating candidates now for a fellowship position dedicated to this research, which has the potential to produce some amazing breakthroughs. Our collaboration could be another example of one plus one equaling more than two. I’m also pretty excited about how the cost of gene sequencing continues to fall. Just a decade ago sequencing cost almost $100 million per genome. Five years ago the cost began a precipitous descent that may soon put sequencing within reach for many patients. The new collaboration investigating the H3.3 mutation, plus access to genomic sequencing at a reasonable cost, changes the whole landscape of our research. These are exciting times indeed, and I remain truly grateful to Elizabeth’s Hope for its...

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Children’s Brain Tumor Project Lab Update: Summer 2012

Posted in About the CBTP, Research, Updates

By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project All of us at the Weill Cornell Pediatric Brain and Spine Center mourn Elizabeth’s passing, a devastating loss to her family and community. Elizabeth’s remarkable vision for this foundation, and our promise to her, motivates us every day in our search for new treatments for gliomatosis cerebri and other rare and inoperable brain tumors of childhood. Elizabeth’s Hope lives on as her legacy, and turning her dream into a reality has been made possible by the outpouring of support from her community—supporters like you. As you know, we are committed to using the latest in genetic medicine and innovative delivery techniques to create new hope for families facing these terrible diagnoses. This summer, Elizabeth’s cancer was the first gliomatosis cerebri tumor from any patient in the world to be completely sequenced, a very proud but bittersweet moment for the scientists in our lab. The process generates a dizzying amount of data, and our lab has an urgent need for a PhD fellow with expertise in bioinformatics to begin to perform the computational analysis. Thanks to the generosity of Elizabeth’s Hope donors, we are now recruiting a scientist to start in the fall to work on gliomatosis cerebri and other rare and inoperable pediatric brain tumors. Your gifts make it possible for us to do the day-to-day work that will one day lead to real solutions. We have also obtained 20 stored gliomatosis cerebri tumor samples from the archives of several leading hospitals around the country. It’s the right way to start, but our research depends upon fresh samples as well as archival ones, so it’s critical to get the word out. We are in constant contact with other research institutions about our work here, and about our commitment to advancing the science in this area. We’re also going to establish a national patient registry where we can track new cases, because examining as many new tumors as we possibly can is critical to finding solutions. Only by finding commonalities in these tumors can we then pursue the best therapeutic agents to attack them. The history of lung cancer research holds a great lesson for us: Laboratory researchers identified a fusion protein that presents itself in about 5 percent of cases. That’s a small percentage, but before this protein was identified those cases were aggressive and intractable, with a survival time of about 90 days from diagnosis. After the protein was found, and a targeted drug was developed, survival times were extended to several years. As we continue to find similar clues within tumors, we can divide patients into groups that will fare better with very specific treatments and continue...

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