I am very proud to be working in the Children’s Brain Tumor Project laboratory, and quite astounded at how fast the initiative has grown. I was appointed as a Fellow in 2012, when I was assigned to work on the role of bone-marrow-derived cells in low-grade glioma transformation. Today, I’m honored to lead the daily operation of our lab’s partnership with the Weill Cornell Institute for Precision Medicine (IPM), which allows us to do exactly the sort of personalized medicine that we dreamed about just a few years ago.
Shortly after our summer issue went to press, Dr. Greenfield and CBTP researchers published a 15-year review of gliomatosis cerebri cases in the Journal of Child Neurology. The paper examined the cases of 10 children seen at Weill Cornell or enrolled in our GC International Registry, alongside 89 children diagnosed with GC reported in the literature between 2000 and 2014. The review documents the kinds of molecular changes seen in gliomatosis cerebri and paves the way for future research. Retrospective reviews like these are invaluable to the research community, as they painstakingly gather data that others can use to initiate new lines of investigation.
Diffuse intrinsic pontine glioma (DIPG) is a complex and challenging tumor. Its location in the brain stem, combined with its diffuse nature, makes it inoperable. No chemotherapy drug has yet been effective against it. Radiation provides only temporary relief before the malignancy returns. And the scarcity of both tumor tissue and research funding has made it difficult for scientists to study it. Recent advances in the OR and in the lab, however, are starting to change the tumor’s grim profile.
For decades, neurosurgeons were reluctant to biopsy pontine gliomas for fear of inflicting devastating neurological harm on their young patients. Stereotactic needle biopsy now makes it possible to biopsy these tumors, not only confirming the diagnosis but also securing tissue samples for research.
At the Children’s Brain Tumor Project laboratory, we now have several distinct patient-derived DIPG cell lines growing in vitro. Using these cell lines, we can study the molecular alterations present in these tumors and select effective molecular targeted therapies to test. We are learning more every day about the genetic mutations, epigenetic alterations, and the activation of stem cell pathways that might be causing these malignancies. (We also have gliomatosis cerebri cell lines growing, but GC cells grow more slowly than DIPG cells do, so it will take a bit longer for them to be ready for testing.)
As we learn more about DIPG’s molecular characteristics, we can apply newly developed high-throughput screening (HTS) techniques to try to match those characteristics with existing FDA-approved drugs. Using HTS, we can examine millions of variables in already-approved oncology drugs in search of promising candidates to test against DIPG. These drugs are in clinical use today for other cancers, and we are testing them on our collection of DIPG cell lines. The goal of the initiative is to identify the most potentially effective drugs for DIPG, and then rapidly transition them to clinical trials.
Perhaps even more significantly, HTS allows us to predict which combinations of oncology drugs would make good candidates to use in synergy against DIPG based on the molecular profile of the tumor cells. (In other cancers, synergistic drug combinations have succeeded when single drugs have failed.) Synergistic drug pairs have special potential for success against chemo-resistant cancer cells. Drugs can be specifically paired to attack the cancer cells on parallel paths, so that when the first encounters drug resistance from the tumor, the second is able to continue on its mission. The combinations can also achieve a desired effect at a lower total dosage, usually with fewer side effects.
The next step is to inject our DIPG cells into animal models, then use convection-enhanced delivery (CED, the technique being used in Dr. Souweidane’s clinical trial) to deliver specially selected drug pairs into the tumor. Since we’ll have very detailed information about the tumor cells, we’ll be able to choose drugs that have the best chance of success against those particular cells. It’s a tremendous first step toward developing personalized treatments that will someday allow us to select the most promising drugs to use in children with DIPG.
As I write this, it’s hard to believe it’s been nearly four years since I received word that the FDA had approved my clinical trial testing the safety of using convection-enhanced delivery (CED) to deliver drugs directly to the site of a DIPG tumor. It seems like the blink of an eye, and in scientific research terms it is. But I know that those four years also represent nearly 800 children who lost their lives to this dreadful disease while we’ve been searching for a cure.
Keeping those children front and center—in my own mind, in the minds of our lab researchers, and most of all in the minds of our families—is a key driver that keeps this project going, and that creates the momentum we need to keep reaching new milestones.
I reached one of those milestones just today, when I operated on the last patient in the trial to receive dose level six. Nearly two dozen children have been treated, without a single significant adverse effect. We are very close to establishing what I have believed for four years: that CED is safe to use in children, and that it can deliver drugs to a tumor in far greater concentrations than can be achieved using traditional chemotherapy.
Now comes the final stage of this trial: dose level seven. After that we hope to expand the trial to more institutions nationwide—treating more children, with a wider range of drugs and dose levels, using single and combination drug therapies tailored specifically to individual tumors.
The cell lines we have growing right now in our lab are providing us with a wealth of information every day about DIPG (see next page for more on these cell lines). We could not being doing this work if it were not for the collaboration among our peers worldwide, the participation of families who are dedicated to finding new treatments, and the generous donors who keep supporting us. I could not be more proud of where we are today, or more excited about where we are headed.
Things are hopping in the lab these days, with new investigations going on and with summer help and new hires giving us the capacity to get more work done. We’ve recently welcomed lab technician and manager Melanie Schweitzer; instructor Ude Macchani, PhD; medical student Shaikha Al-Qahtani; research assistant Rachel Yanowitch; summer clinical interns Samantha O’Brien and Nicole Michelson; and summer marketing intern Michael Sapunor.
Medical student Linda Wu is only 25, but she has a long-standing interest in oncology and neuroscience. Wu is a graduate of Cornell University in Ithaca, where she majored in biology with a concentration in neuroscience. She was then accepted into Weill Cornell Medical College, where she has completed three of her four years of study. Between her first and second years she worked on a pediatric neurology research project, and this summer she joins the CBTP lab full-time for a year to work on Dr. Souweidane’s DIPG research.
It might sound strange for a medical student to be taking a year off from her studies instead of spending that year completing her medical degree, but it’s not at all surprising for Wu. Her passion for oncology research made this an easy choice once she heard about the new pediatric neurosurgery Medical Student Fellowship, made possible by a grant from the Rudin Foundation. After her application was accepted by Dr. Souweidane, Wu immediately dug into the project started by Ranjodh Singh (who returns to his medical studies this fall after his own year in the CBTP lab).
Singh spent the past year testing combinations of drugs to fight DIPG; Wu will continue that work by focusing on how tumors might develop resistance to those drugs. Her research will involve monitoring changes along the molecular pathway and investigating which inhibitors would work to defeat the tumor’s resistance.
Wu will return to medical school in the fall of 2016 to complete her fourth year and earn her medical degree.
One of the interesting things about scientific research is that you don’t always know what you’ll find when you start looking at something, and you can’t predict what seemingly minor discovery will turn out to be a stepping stone to a much larger one. That’s what makes it so important to gather data, analyze it, and turn it over dozens of times, looking for clues you may not recognize at first or new questions you hadn’t previously thought to ask.
We’re proud to be contributing to the advancement of neuroscience at a faster pace these days, as the additional resources made possible by your donations allow us to gather and analyze more and more data, with some surprising results. Our team recently published three papers on new findings that add to the knowledge base on pediatric brain tumors:
The September issue of Neurosurgery will report on a study directed by Dr. Greenfield. This new study looked at 97 children—the single largest cohort of children ever studied—with a malignant brain tumor called glioblastoma. While beginning a more detailed genomic analysis, they first investigated more mundane parts of their clinical course such as surgery and radiation. The data confirmed in children what was already known for adults, which is that total resection leads to longer survival times than partial. That may be intuitive, but studying the data produced another, more puzzling result: When tumors can be totally removed, the improvement in outcomes is significantly greater for girls than for boys. Why? We don’t know… yet. This gives the CBTP an important clue as we begin analyzing specific parts of these tumors’ chromosomes and genomes, looking for potential clues as to where the gender bias might arise and if this could offer new targets to investigate as therapeutic options.
The July issue of the Journal of Neurosurgery Pediatrics reports on a case of a young man whose MRI had shown a tumor in the region of the midbrain called the tectum. An endoscopic biopsy, however, revealed additional lesions on the floor of the third ventricle that turned out to be low-grade gliomas. This surprising find not only points out limitations of MRI (which is an excellent imaging tool), but also suggests the tumors spread through the cerebrospinal fluid. Analyzing these samples genetically also offers a fascinating glimpse into a tumor that looks benign, but that spreads like a malignant tumor! All these clues are part of the outside-the-box thinking that our genomic tools and resources allow us to investigate. Dr. Souweidane is the senior author of this paper.
The June issue of the Journal of Neurosurgery includes a study that looked at radionecrosis, a devastating complication of external beam radiation that causes cell death months or even years after treatment, making radiation therapy particularly risky for young children. This new study, co-authored by Dr. Kramer of Memorial Sloan-Kettering and Dr. Souweidane, looked at the incidence of radionecrosis in young patients treated with intraventricular compartmental radio-immunotherapy (cRIT) instead of or in addition to external beam radiation. The study found none of the neurological damage caused by radiation necrosis in those treated with cRIT. This new finding makes radioimmunotherapy a potentially safer weapon against pediatric brain tumors than external beam therapy. It’s part of our commitment to finding not only more effective but also gentler therapies for our children.
Each finding we can publish not only helps our own team as we strive to develop new therapies for rare and inoperable brain tumors, it also goes forth into the scientific community at large, where it just might mean a safer treatment for a child today, or a new piece of the puzzle that will fit into another piece a year from now. We’re proud to be contributing, and we thank our donors for making it possible.
Medical student Scott Connors will continue his investigations into recurrent pediatric ependymoma in the CBTP lab this summer, funded by a fellowship grant from the St. Baldrick’s Foundation. St. Baldrick’s, a longtime supporter of the Children’s Brain Tumor Project, awarded the grant for research into the genomics and epigenomics of ependymoma. Much like DIPG and GC, ependymomas—which arise from ependymal cells that line the ventricles of the brain—are rare brain tumors that have been poorly studied to date compared with other pediatric cancers. Thanks to an outpouring of support from the family and friends of Campbell Hoyt, the CBTP has been able to expand seminal studies specific to understanding why recurrent ependymoma is so difficult to cure. The St. Baldrick’s grant will allow us to redouble our efforts on that research and lay the groundwork for future investigations and potential clinical trials.
The Alex’s Lemonade Stand Foundation has awarded a $5,000 grant to Melinda Wang, a medical student at Weill Cornell Medical College, to conduct research into the distribution of the therapeutic agent delivered during convection- enhanced delivery (CED). Dr. Souweidane’s clinical trial for DIPG has been testing the safety of using CED to get tumor-fighting drugs directly to the site of a brainstem tumor. A special contrast agent can trace large molecules as the drugs are infused, but there has not been a reliable way to measure the concentration of the smallest molecules. Wang, a first-year medical student, will modify two small-molecule kinase inhibitors, dasatinib and everolimus, to allow them to be monitored by positron emission tomography (PET) and near-infrared fluorescence (NIRF). This will provide, for the first time, accurate real-time images of how small-molecule drugs perform when infused during a CED procedure.
This issue’s 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. (Read more about both conferences on page 2.)
This month, 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 CBTP.