Children’s Brain Tumor Project Lab Update: Summer 2014

Posted in About the CBTP, Research, Updates

By Prajwal Rajappa, M.D. Pediatric Brain Tumor Fellow Weill Cornell is one of 200 institutions that make up the Children’s Oncology Group (COG), the world’s premier organization dedicated to eradicating childhood cancer. Dr. Mark Souweidane and Dr. Prajwal Rajappa lead the Weill Cornell Pediatric Brain and Spine Center’s participation in a long-term study of brain tumor tissue samples collected from pediatric patients around the world, with the goal of understanding the molecular profile of these tumors. This lab update about our COG project was contributed by Dr. Rajappa. This COG study is extremely important given the lack of effective treatments available for pediatric brain tumor patients. We are collecting brain and spinal tumor tissue from pediatric patients treated at COG facilities around the world, providing a repository for long-term storage of those specimens. This study allows us to make specimens available to expert researchers both here in the United States and abroad who are working to understand the biology of these tumors. These repository-driven studies utilizing human tissue serve as the platform for meaningful translational research, which relies on laboratory findings that can be quickly applied to develop new treatment options. The rapidly evolving science of human genomics has the potential to change how physicians diagnose and treat cancer, but molecular studies require access to tumor tissue, which has been extremely limited—especially when the tumors are rare. There’s a particular shortage of pediatric tissue specimens available for ependymomas, thalamic gliomas, brainstem gliomas, diffuse pontine gliomas, gliomatosis cerebri, low-grade gliomas, and primary GBMs. The limited number of specimens available for research within any single institution can make it impossible to conduct statistically powerful and high-impact molecular research. Therefore, participation from multiple institutions is essential. Here at Weill Cornell, with a world-class pediatric service that draws patients from near and far, we have gathered a wide variety of samples of many pediatric brain and spine diseases in our repository, making us one of the top member institutions in the COG. In fact, in our first full year of participation in this study (2012), Weill Cornell ranked eighth out of 142 participating institutions in terms of number of pediatric patient samples enrolled. This year, we are poised for our highest patient enrollment on study. As shown in the pie chart at right, we have accrued a wide array of pediatric central nervous system (CNS) disease entities in our departmental repository that will serve as valuable material for further genomic sequencing and translational research. Within Weill Cornell, we have developed streamlined collaborations with other departments, such the department of pathology, which will ultimately advance our understanding of the biology of pediatric brain tumors and further initiate multi-disciplinary studies. Solidifying our role at COG,...

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Children’s Brain Tumor Project Lab Update: Spring 2014

Posted in About the CBTP, Research, Updates

By Mark M. Souweidane, MD Co-Director, Children’s Brain Tumor Project I’ll never forget May 1, 2012 — that was the day I performed the very first procedure in a new clinical trial testing convection-enhanced delivery (CED) of a therapeutic agent in a child with DIPG. More than ten years of my prior lab work, including bench research and animal testing, had me absolutely convinced that this was a safe procedure. Still, with anything so completely new there’s just that tiny seed of doubt, the faintest whisper of “what if…” What I was not prepared for were the emotional ties that quickly took hold of me. The little girl in the OR that day was Caitlin Downing, whom I had come to love in just a few short weeks of knowing her and her family. Hugs, insightful questions, and smiles from this 5-year-old were gripping. Caitlin’s sister, Courtney, had even joined her on one of her preoperative visits to New York so that she could approve of the doctor who would offer hope. Imagine my relief when the procedure went exactly as expected, and imagine my heartbreak several months later when the tumor came back to claim Caitlin’s life. But her successful surgery validated every effort that went into this translational project and left no doubt that we should push on. Today we find ourselves in an exciting position: With 13 children treated so far (all of whom have tolerated the treatment well, with no adverse effects), we have answered critical questions about the technical, surgical, and diagnostic aspect of this drug delivery tactic. Early results have raised awareness from oncologists, neuro-surgeons, radiologists, and pharmacologists from all over the world. The momentum is building rapidly. So encouraging are the results that we have decided to request a continuation of the study. If the continuation is approved, we will plan to treat a minimum of 12 more children at escalating doses. The study is being positively viewed on a national level. The preliminary results of this trial were presented to the Pediatric Brain Tumor Consortium (PBTC) in Atlanta last month. That group is highly interested in moving the strategy into a “group-wide” study and has assembled a working group, which I am leading, to formulate the best plan. Even as we modify the current strategy, we are continuing our laboratory and clinical efforts in different arenas. As an example, we are using other strategies for bypassing the blood-brain barrier, which is what prevents us from getting adequate doses of cancer-fighting molecules to a tumor site. In addition to testing CED, we are also pursuing another potential route, using super-selective intra-arterial chemotherapy to deliver medicine directly into the blood vessels of the...

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Children’s Brain Tumor Project Lab Update: December 2013

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By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project It’s hard for me to believe that two years have gone by since Elizabeth’s Hope was born, allowing us to launch the Children’s Brain Tumor Project. In scientific research terms, this has been the blink of an eye. I am so very grateful for your support—this truly is a dream come true for me, and some day we will be able to make a significant impact on the care of children facing brain tumors. Anniversaries always make you look back and think about where you’ve been, and our list of accomplishments over the past two years is considerable. Here are some of the highlights of our first two years: 2011-2012 Elizabeth’s tumor was the very first sample of gliomatosis cerebri ever subject to genomic analysis, and it yielded a treasure trove of information about the genetic mutations associated with her tumor. Since then we have been able to sequence several additional tumors, searching for what they have in common with Elizabeth’s, and where they diverge. This hunt for patterns and data is what will help us unlock the mystery of this rare tumor. Only weeks after Elizabeth’s Hope was founded, my colleague Dr. Mark Souweidane received FDA approval to begin a groundbreaking trial testing the safety of convection-enhanced delivery (CED) of therapeutic agents for pontine gliomas (DIPG). He treated the first patient in May of 2012 and has treated eight more children since then, with zero toxicity. Testing different agents, at different doses, will generate the data we need in the coming months and years. In the fall of 2012, a basic science researcher named C. David Allis, Ph.D., was investigating and documenting a DNA histone called H3.3. Much to everyone’s surprise, it was discovered that H3.3 mutations are found in pediatric gliomas. Dr. Allis and I are now collaborating on a new project to try to find out why the mutation causes gliomas — including gliomatosis cerebri — to develop. I was honored to share in a Starr Cancer Consortium grant given to Dr. Allis to pursue the research. I have a two-year, $112,000 grant for 2013 and 2014. 2013 In January 2013, the Institute for Precision Medicine opened its doors at NewYork-Presbyterian/Weill Cornell Medical Center. This cutting-edge research hub is exploring how to develop optimal targeted, individualized treatment based on each patient’s genetic profile. This is extraordinarily significant for Elizabeth’s Hope and the Children’s Brain Tumor Project, as it brings the ability to sequence tumors right onto our campus and spares us the cost of buying new machinery. Our gifts can be used for the bioinformatics staff members we need to interpret the data, rather than on...

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Children’s Brain Tumor Project Lab Update: Fall 2013

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By Jeffrey Greenfield, MD, PhD Director, Children’s Brain Tumor Project We have some extremely exciting news to report this month: Yujie Huang, PhD, of our Children’s Brain Tumor Project laboratory, has been awarded a three-year, $400,000 grant from the Department of Defense. Dr. Huang was awarded the grant for a project called “Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors.” Gliomatosis cerebri is one of the most difficult — if not the most difficult — to cure of all astrocytic brain tumors, so getting this project funded is a significant step forward for us. News like this makes it more and more clear how critical the support of Elizabeth’s Hope is to us. Department of Defense grants are not easy to secure, and an award of this size required us to file an application with supporting data based on previous research. That data assures the DoD that its grant money is going to projects that are based on sound science and have good chance of success. How could our lab have done the foundational work, and generated the data, if not for you, our loyal supporters? Even more exciting, some of the data used in support of this grant application was generated by Emma Vartanian, who joined the lab on a summer fellowship from the Saint Baldrick’s Foundation. As you may recall from our Spring 2013 newsletter, Emma’s project uses mouse models to study the effects of an inhibitor drug on gliomas, with the goal of preventing low-grade tumors from progressing into fatal ones. If we can learn how to stop bone marrow cells from signaling the distant tumor to grow, we may be able to keep low-grade gliomas from developing into high-grade tumors like gliomatosis cerebri. Under Dr. Huang’s guidance this summer, Emma and the team initiated the transplant phase of the study and performed bone marrow transplants on more than 20 animals. Now those mice will be treated with an experimental inhibitor drug to test its ability to limit tumor growth. As the treatment progresses in Dr. Huang’s newly funded phase of this study, our research team will be able to analyze how the transplanted bone marrow-derived cells move and participate in tumor progression. We already have histological and radiographic data, in the form of brain tissue slides and MRI images, suggesting far better tumor outcomes and survival patterns in drug-treated transplant mice, as compared to untreated control animals. This is exciting stuff indeed. I am so energized by how our work is all coming together. With Elizabeth’s Hope making our lab work possible, we gave St. Baldrick’s the confidence to award us the summer fellowship. With...

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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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