“I get strength from kids and families, strength like that shown by Nick and his family,” answered Roger Packer, M.D., when Quicken Loans owner Dan Gilbert asked how he copes with the stress of seeing children struggling with brain tumors and other neurological problems every day.
Dr. Packer, senior vice president of the Center for Neuroscience and Behavioral Medicine at Children’s National Health System, joined Mr. Gilbert and his son, Nick, who was treated for neurofibromatosis at Children’s National, for a panel discussion at the recent Crain’s Health Care Heroes event. The discussion focused on Nick Gilbert, now a college student, and how he has stayed positive while undergoing intense treatments for neurofibromatosis since he was 15 months old.
Dr. Packer met Nick at age 10, when he first came to Children’s National for its world-renowned expertise in neurofibromatosis research and care. After their experiences, the Gilberts generously supported the creation of the Gilbert Family Neurofibromatosis Institute at Children’s National Health System to continue research into new and innovative treatments for the disorder.
Mr. Gilbert credits Dr. Packer with taking on difficult cases and having a positive impact on both Nick and himself. “When other doctors give up on patients, he intervenes with magic and saves lives.”
The reason, according to Dr. Packer, is that kids like Nick “don’t want to give up.” Thankfully, he notes, better tools to treat diseases like cancer and neurofibromatosis have finally arrived. “There are remarkable advances that were not possible five years ago,” he said.
One of 16 steering committees formed in response to the recommendations of the Clinical Trials Working Group mandated by the National Cancer Advisory Board (NCAB), the BMSC’s goal is to promote the best clinical and translational research for patients with brain cancer by critically reviewing Phase 2 and Phase 3 clinical trial concepts.
Dr. Packer also directs the Brain Tumor Institute and is principal investigator for the Pediatric Brain Tumor Consortium (PBTC), formed under the auspices of the National Cancer Institute (NCI). He has worked closely with the NCI and the National Institute of Neurological Disorders and Stroke (NINDS), and has served on multiple committees setting the directions for neurologic clinical and basic science research for the future. Much of Dr. Packer’s clinical research has been translational in nature. He has been part of studies evaluating the molecular genetics of childhood and adult neurologic diseases, and has also coordinated the first gene therapy study for children with malignant brain tumors in the U.S.
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This year, more than 4,600 children and adolescents (0-19 years) will be diagnosed with a pediatric brain tumor. Brain tumors have now passed leukemia as the leading cause of pediatric cancer-related deaths. Despite this, there has never been a drug developed specifically to treat pediatric brain tumors and for many pediatric brain tumor-types, no standards of care or effective treatment options exist. In particular, pediatric high-grade gliomas have no standard of care and a very low survival rate.
To combat this, the National Brain Tumor Society (NBTS), the largest nonprofit dedicated to the brain tumor community in the United States, with its partner, the St. Baldrick’s Foundation, the largest private funder of childhood cancer research grants, as well as several world-renowned experts in the field of pediatric neuro-oncology, announced a new awareness and fundraising campaign to support a major translational research and drug discovery program. The campaign, called “Project Impact: A Campaign to Defeat Pediatric Brain Tumors,” was unveiled at the National Press Club in Washington, DC, on Sept. 12. Watch the live streaming replay.
Children’s National brain tumor expert leads the way
The collaborative hopes to improve clinical outcomes for pediatric brain tumor patients and inform the development of the first standard of care for treating pediatric high-grade gliomas, including DIPG – the deadliest of pediatric cancers.
Roger J. Packer, M.D., Senior Vice President of the Center for Neuroscience and Behavioral Medicine and Director of Brain Tumor Institute at Children’s National Health System, serves as the Scientific Director of the Defeat Pediatric Brain Tumors Research Collaborative.
“Treatment of pediatric high-grade gliomas has been extremely frustrating with little progress made over the past quarter century,” said Dr. Packer. “New molecular insights provide hope that therapies will be dramatically more effective in the very near future. In the last two years alone we have had great breakthroughs, primarily identifying genes which are critical in development of new pediatric treatments. But we need to maintain forward momentum from discovering the molecular and genetic underpinnings of these tumors, to understanding how these changes drive these tumors, and to ultimately developing effective, biologically precise therapies. This is a major opportunity for the field, patients, and their families.”
Pediatric high-grade gliomas make up to 20 percent of all pediatric brain tumors with roughly 500-1,000 new diagnoses every year. These tumors are WHO Grade III and Grade IV gliomas, including: pediatric glioblastoma (GMB); glioma malignant, NOS; pediatric anaplastic astrocytoma; anaplastic oilgodendroglioma; giant cell glioblastoma; gliosarcoma; and diffuse intrinsic pontine gliomas (DIPG).
David Arons, CEO of the National Brain Tumor Society said, “Researching and developing new treatments for pediatric brain tumors is a particularly challenging task, which faces multiple – but interrelated – barriers that span the research and development spectrum from small patient populations, lack of effective preclinical models, to complex basic biology, regulatory hurdles and economic disincentives. To overcome these complex challenges, and get better treatments to patients, we needed to create an equally sophisticated intervention. We believe that having groups with complementary skills work together in a coordinated effort, sharing data and expertise, and tackling the problem from multiple angles as one team is the starting point for greater and faster progress.”
How the collaborative is set up
The model for the collaborative consists of scientists and researchers who will each lead interrelated “Cores” to work on critical areas of research simultaneously and in concert with one another, encouraging sharing of findings real time. This design allows new findings to quickly move onto the next stage of research without barriers or other typical delays, significantly speeding up the research process.
Dr. Packer said the goal of this research collaboration is to work with pediatric brain tumor researchers from around the world to discover new treatments for children in the next two to three years, instead of the next decade.
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Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.
For more than four decades, clinicians around the nation have been giving the parents of pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) the same grim prognosis. In the past five years, there has been an explosion of innovative research at Children’s National Health System and elsewhere that promises to change that narrative. That’s because the black box that is DIPG is beginning to divulge its genetic secrets. The new-found research knowledge comes as a direct result of parents donating specimens, judicious shepherding of these scarce resources by researchers, development of pre-clinical models, and financing from small foundations.
From just 12 samples six years ago, Children’s National has amassed one of the nation’s largest tumor bio banks – 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG.
Such donated specimens have led to the identification of H3K27M mutations, a groundbreaking finding that has been described as the single-most important discovery in DIPG. Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.
Histone mutations (also referred to as oncohistones) are sustained in the tumor throughout its molecular evolution, found a research team led by Javad Nazarian, Ph.D. Not only were H3K27M mutations nearly ubiquitous in all samples studied, the driver mutation maintained partnerships with other secondary mutations as DIPG tumor cells spread throughout the developing brain. Children’s National researchers have identified tumor driver mutations and obligate partner mutations in DIPG. They are examining what happens downstream from the histone mutation – changes in the genome that indicate locations they can target in their path toward personalized medicine. The value of that genomic knowledge is akin to emergency responders being told the specific house where their help is needed, rather than a ZIP code or city name, Dr. Nazarian says. While there is currently no effective treatment for DIPG, new research has identified a growing number of genomic targets for future therapeutics.“That changed the dynamic,” says Dr. Nazarian. “In DIPG clinical research, nothing had changed for 45 years. Now we know some of the genomic mutations, how the tumor was evolving – gaining new mutations, losing mutations. With precision medicine, we can target those mutations.”
Another study led by neuro-oncologist Eugene Hwang, M.D., reported the most comprehensive phenotypic analyses comparing multiple sites in a young girl’s primary and metastatic tumors. This study showed that despite being uniform, small molecules (mRNA) could be used to distinguish an evolved tumor from its primary original tumor mass.Key to this multidisciplinary work is collaboration across divisions and departments. Within the research lab, knowledge about DIPG is expanding.
Each member of the DIPG team – neurosurgery, neuro-oncology, immunology, genomics, proteomics – feeds insight back to the rest of the team, accelerating the pace of research discoveries being translated into clinical care. Among the challenges that the team will address in the coming months is outmaneuvering tumors that outsmart T-cells (immune cells).
“What is happening in the checkpoint inhibitor field is exciting,” says Catherine M. Bollard, MBChB, MD, Chief of Allergy and Immunology and Director of the Program for Cell Enhancement of Technologies for Immunotherapy. “The inhibitors work by reversing the ‘off’ switch – releasing the brake that has been placed on the T-cells so they can again attack multiple tumor proteins. The next exciting step, and novel to Children’s National, will be to combine this approach with T-cell therapies specifically designed to attack the DIPG tumors. Unlike the use of combination chemotherapy, which has had a limited impact, we hope that the novel combination of immunotherapeutic approaches will offer the hope of a potential cure.”
Dr. Hwang, another member of the multidisciplinary team, adds: “When you’re looking at the landscape – for me, at least – it starts and ends with how my patients are doing. There are kids for whom we have had great successes in improving survival rates in some cancers, like leukemia, and some where the needle has moved nowhere, like DIPG. We’re still trying to figure out the whole picture of who responds. The immune system is present in all kids. Its ability to attack is present in all kids.”
Children’s National is one of the few hospitals in the nation that conducts brainstem biopsies for DIPG and does so with very little chance of complications. The pons is like a superhighway through which nerves pass, making it instrumental in smooth operation of such vital functions as breathing, heart rate, sleeping, and consciousness. The ability of neurosurgeon Suresh Magge, MD, to perform such sensitive biopsies upends conventional wisdom that these procedures were inherently too dangerous. Within two weeks of diagnosis, genomics analyses are run to better understand the biology of that specific tumor. Within the following weeks, the tumor board occurs, and patients with DIPG are placed on therapy that best targets their tumor’s mutations.
The black box that is diffuse intrinsic pontine glioma is beginning to divulge its genetic secrets.
Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of children with DIPG die within two years of diagnoses. Biomarkers that point to DIPG – like the copies of DNA that tumors shed and leave behind in the bloodstream – could enable creation of liquid biopsies, compared with today’s surgical approach.
Children’s also is making a concerted effort to create preclinical models of DIPG. Preclinical models will be used to winnow the field of potential therapeutics to the candidates most likely to help children survive DIPG. The preclinical tumor cells will be labeled with luciferase – enzymes that, like photoproteins, produce bioluminescence – permitting the researcher to visually see the formation, progression, and response of DIPG tumors to treatment in preclinical settings.
These preclinical models could be used to test multiple drug combinations in conjunction with radiation therapy. Molecular signatures and response to treatment could then be assessed to learn how the tumor resists therapy. Due to the obligate partnerships between driver mutations and secondary mutations, the research team already knows that effective DIPG medicines will need more than one target. If there were a single mutation, that would be like having a single master key to open many locks. Multiple mutations imply that more than one key will be needed. Thus, the search for cures for DIPG will necessitate taking a multi-pronged approach.
Combined drug regimens, including those created with proprietary technology, with or without radiation, will be keys to targeting myriad mutations in order to kill tumors where they are. Those drug combinations that demonstrate they can do their jobs – slowing tumor growth, increasing chances of survival, taming toxicity – will be selected for clinical application.
Immunotherapy leverages T-cells, the immune system’s most able fighters, to help in the overall goal of extending patients’ survival. One of the most challenging aspects of pediatric brain tumors is the body does a very good job of shielding the brain from potential pathogens. Precise drug delivery means finding innovative ways for therapeutics to cross the blood-brain barrier in order to reach the tumor. The team has identified one such potential target, the protein NG2, which may represent a good target for immune therapy. The protein is expressed in primitive cells that have not become specialized – meaning there may be an opportunity to intervene before it is driven to become a tumor cell.
What’s Known Needle biopsies help to guide diagnosis and targeted therapies for diffuse intrinsic pontine gliomas (DIPGs), which make up 10 percent to 15 percent of all pediatric brain tumors but carry a median survival of 9 to 12 months. This dismal survival rate compares with a 70 percent chance of children surviving other central nervous system tumors five years post diagnosis. In DIPG, tumors appear in the pons, an area of the brain that houses cranial nerve nuclei. Surgical options are limited. Spatial and temporal tumor heterogeneity is a major obstacle to accurate diagnosis and successful targeted therapy.
What’s New
The team sought to better define DIPG heterogeneity. They analyzed 134 specimens from nine patients and found that H3K27M mutations were ubiquitous in all 41 samples with oncogenic content, and always were associated with at least one partner driver mutation: TP53, PPM1D, ACVR1 or PIK3R1. These H3K27M mutations are the initial oncogenic event in DIPG, writes the research team led by Children’s National Health System. “Driver” mutations, such as H3K27M, are essential to begin and sustain tumor formation. This main driver partnership is maintained throughout the course of the disease, in all cells across the tumor, and as tumors spread throughout the brain. Because homogeneity for main driver mutations persists for the duration of illness, efforts to cure DIPG should be directed at the oncohistone partnership, the authors write. Based on early tumor spread, efforts to cure DIPG should aim for early systemic tumor control, rather focused exclusively on the pons.
Questions for Future Research Q: If a larger sample size were analyzed, what would it reveal about the true heterogeneity/homogeneity status of DIPGs? Q: “Accessory” driver mutations are not absolutely essential but do help to further promote and accelerate tumor growth. What is their precise role?
Source: “Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pontine Glioma.” H. Nikbakht, E. Panditharatna, L.G. Mikael, R. Li, T. Gayden, M. Osmond, C.Y. Ho, M. Kambhampati, E.I. Hwang, D. Faury, A. Siu, S. Papillon-Cavanagh, D. Bechet, K.L. Ligon, B. Ellezam, W.J. Ingram, C. Stinson, A.S. Moore, K.E. Warren, J. Karamchandani, R.J. Packer, N. Jabado, J. Majewski, and J. Nazarian. Published by Nature Communications on April 6, 2016.
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