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Jeffrey Dome

Treating Wilms Tumor with vincristine and irinotecan

Jeffrey Dome

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” says study leader Jeffrey S. Dome, M.D, Ph.D.

Wilms tumor, the most common kidney cancer of childhood, may be classified into different subtypes based on its appearance under the microscope. The “favorable histology” subtype is associated with an excellent survival rate of approximately 90%, whereas the “diffuse anaplastic” subtype is associated with survival rates of only 55% for patients with stage II-IV disease.

The Children’s Oncology Group AREN0321 study, led by Jeffrey S. Dome, M.D, Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, tested the anti-tumor activity of the chemotherapy combination vincristine and irinotecan in patients with metastatic diffuse anaplastic Wilms tumor.

The study also evaluated whether a new treatment regimen containing carboplatin in addition to the currently used agents (vincristine, doxorubicin, cyclophosphamide and etoposide) would improve patient outcomes. The results, published in the March 5th issue of the Journal of Clinical Oncology, showed that the vincristine/irinotecan combination is highly active. Out of the group, 78% of patients who received this combination had an objective tumor response.

The study also demonstrated that additional chemotherapy drugs can reduce the rate of relapse, but it is likely that we have reached the limit of what children can tolerate. “Future gains will likely be made by using agents with novel mechanisms of action, such as immunotherapy and new drugs that target the molecular abnormalities of Wilms tumor cells,” says Dr. Dome.

Moreover, the additional chemotherapy agents improved cancer-free survival rates to levels unprecedented for diffuse anaplastic Wilms tumor. However, the decrease in relapse rate came at the cost of increased toxicity.

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” Dr. Dome added.

Vote for STAT Madness

It’s a three-peat! Children’s National again competes in STAT Madness

Vote for STAT Madness

Children’s National Hospital collects patients’ blood, extracts T-cells and replicates them in the presence of specific proteins found on cancer cells which, in essence, teaches the T-cells to target specific tumor markers. Training the T-cells, growing them to sufficient quantities and ensuring they are safe for administration takes weeks. But when patients return to the outpatient clinic, their T-cell infusion lasts just a few minutes.

For the third consecutive year, Children’s National was selected to compete in STAT Madness, an annual bracket-style competition that chooses the year’s most impactful biomedical innovation by popular vote. Children’s entry, “Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes,” uses the body’s own immune system to attack and eliminate cancer cells in pediatric and adult patients with solid tumor malignancies.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

An estimated 11,000 new cases of pediatric cancer were diagnosed in children 14 and younger in the U.S. in 2019. And, when it comes to disease, cancer remains the leading cause of death among children, according to the National Institutes of Health. An enterprising research team led by Children’s National faculty leveraged T-cells – essential players in the body’s immune system – to treat pediatric and adult patients with relapsed or refractory solid tumors who had exhausted all other therapeutic options.

“We’re using the patient’s own immune system to fight their cancer, rather than more traditional chemotherapy drugs,” says Catherine M. Bollard, M.D., director of the Center for Cancer & Immunology Research at Children’s National and co-senior author of the study. “It’s more targeted and less toxic to the patient. These T-cells home in on any cancer cells that might be in the body, allowing healthy cells to continue to grow,” Dr. Bollard adds.

That means patients treated in the Phase I, first-in-human trial didn’t lose their hair and weren’t hospitalized for the treatment. After a quick clinical visit for their treatment, they returned to normal activities, like school, with good energy levels.

“With our specially trained T-cell therapy, many patients who previously had rapidly progressing disease experienced prolonged disease stabilization,” says Holly J. Meany, M.D., a Children’s National oncologist and the study’s co-senior author. “Patients treated at the highest dose level showed the best clinical outcomes, with a six-month, progression-free survival of 73% after tumor-associated antigen cytotoxic T-cell (TAA-T) infusion, compared with 38% with their immediate prior therapy.”

The multi-institutional team published their findings from the study online July 29, 2019, in the Journal of Clinical Oncology.

“Our research team and our parents are delighted that some patients treated in our study continue to do well following T-cell therapy without additional treatment. In some cases, two years after treatment, patients do not appear to have active disease and are maintaining an excellent quality of life,” says Amy B. Hont, M.D., the study’s lead author. “One of these was a patient whose parents were told his only other option was palliative care. Our innovation gives these families new hope,” Dr. Hont adds.

The 2020 STAT Madness #Core64 bracket opened March 2, and the champion will be announced April 6.

In addition to Drs. Hont, Meany and Bollard, Children’s National co-authors include C. Russell Cruz, M.D., Ph.D., Robert Ulrey, MS, Barbara O’Brien, BS, Maja Stanojevic, M.D., Anushree Datar, MS, Shuroug Albihani, MS, Devin Saunders, BA, Ryo Hanajiri, M.D., Ph.D., Karuna Panchapakesan, MS, Payal Banerjee, MS, Maria Fernanda Fortiz, BS, Fahmida Hoq, MBBS, MS, Haili Lang, M.D., Yunfei Wang, DrPH, Patrick J. Hanley, Ph.D., and Jeffrey S. Dome, M.D., Ph.D.; and Sam Darko, MS, National Institute of Allergy and Infectious Diseases.

Financial support for the research described in this post was provided by the Children’s National Hospital Heroes Gala, Alex’s Army Foundation, the Children’s National Board of Visitors and Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, the Children’s National Research Institute Bioinformatics Unit, the Clinical and Translational Science Institute and the National Institutes of Health under award No. UL1-TR001876.

4th International Symposium on hypothalamic hamartomas

Children’s National co-hosts the 4th International Symposium on hypothalamic hamartomas

The Children’s National Hospital’s Comprehensive Pediatric Epilepsy Program co-hosted the 4th International Symposium on Hypothalamic Hamartomas held in September 2019 in Washington, D.C.

The 2019 Symposium focused on the psychiatric, neuropsychological, neurological and endocrinological comorbidities of Hypothalamic Hamartomas (HH). The participants also looked at treating the whole person – in addition to the tumor – covering the cognitive, physical, emotional and intellectual impacts of HH.

4th International Symposium on hypothalamic hamartomas

Attendees at the 4th International Symposium on Hypothalamic Hamartomas.

Presenters at the Symposium included experts from around the world, such as Children’s National’s Chief of the Divisions of Child Neurology and of Epilepsy and Neurophysiology,, William D. Gaillard, M.D., who moderated the entire event and served as the HH Symposium Chair on the Symposium Steering Committee.  Dr. Gaillard also facilitated a presentation titledDeveloping a New Paradigm for Assessing, Surveilling, & Treating HH Comorbidities” and another presentation titled, “Set 3 Year Research Roadmap & Top Priorities.”

Senior Vice President for the Center for Neuroscience & Behavioral Health, Roger Packer, M.D., also presented at the event on treatments being used in other hypothalamic hamartoma syndromes which may possibly have opportunities for success with treatment of HH.

Malignant peripheral nerve sheath tumors

Clinical Trial Spotlight: Searching for effective therapies for malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the most common malignancy associated with neurofibromatosis type 1 (NF1).

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the most common malignancy associated with neurofibromatosis type 1 (NF1). Half of all MPNST are seen in NF1 patients, and MPNST is a leading cause of mortality in young patients with NF1. Researchers led by AeRang Kim, M.D., Ph.D., a pediatric oncologist at Children’s National Hospital, are now searching for a medical treatment for this rare disease that currently has dismal survival rates.

“Through consortia efforts, we’ve been able to open and accrue in single histology trials of really rare diseases such as MPNST for which there are no known curative therapies other than surgery, and surgery is very difficult or not feasible in many patients,” says Dr. Kim, the principal investigator for the SARC031 trial sponsored by the Sarcoma Alliance for Research through Collaboration. “In this trial in particular, our hope is to find a new therapy that will benefit patients with MPNST for which we have no known effective medical therapies.”

Using a combination of drugs that target specific pathways involved in MPNST growth, Dr. Kim and colleagues at four other institutions offering the SARC031 trial will monitor patients to see if the drugs shrink, slow down or stop the growth of MPNSTs. Based on preclinical data demonstrating substantial MPNST shrinkage in mice treated with a combination of MEK and mTOR inhibitors, SARC031 is a trial of the MEK inhibitor selumetinib in combination with the mTOR inhibitor sirolimus for patients with unresectable or metastatic MPNST. The primary objective is to determine the clinical benefit of the combination.

SARC031: A Phase 2 Trial of the MEK Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Combination with the mTOR Inhibitor Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors

  • PI: AeRang Kim, M.D., Ph.D.
  • Title: SARC031: A Phase 2 Trial of the MEK Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Combination with the mTOR Inhibitor Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors
  • Status: Recruiting

For more information about this trial, contact:

AeRang Kim, M.D., Ph.D.
202-476-2800
AeKim@childrensnational.org

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

pastel colored DNA strands

Germline microsatellite genotypes differentiate children with medulloblastoma

pastel colored DNA strands

A new study suggests that medulloblastoma-specific germline microsatellite variations mark those at-risk for medulloblastoma development.

Brian Rood, M.D., oncologist and medical director at the Brain Tumor Institute, and Harold “Skip” Garner, Ph.D., associate vice provost for research development at Edward Via College of Osteopathic Medicine, published a report in the Society for Neuro-Oncology’s Neuro-Oncology Journal about using a novel approach to identify specific markers in germline (non-tumor) DNA called microsatellites that can differentiate children who have the brain tumor medulloblastoma (MB) from those who don’t.

“Ultimately, the best way to save children from brain tumors and prevent them from bearing long-term side effects from treatment is to prevent those tumors from occurring in the first place,” says Dr. Rood. “New advancements hold the potential to finally realize the dream of cancer prevention, but we must first identify those children at-risk.”

While analyzing germline sequencing data from a training set of 120 MB subjects and 425 controls, the doctors identified 139 individual microsatellites whose genotypes differ significantly between the groups. Using a genetic algorithm, they were able to construct a subset of 43 microsatellites that distinguish MB subjects from controls with a sensitivity and specificity of 92% and 88% respectively.

“We made discoveries in an untapped part of the human genome, enabled by unique bioinformatics data mining approaches combined with clinical insight,” said Dr. Garner. “Our findings establish new genomic directions that can lead to high accuracy diagnostics for predicting susceptibility to medulloblastoma.”

What the doctors discovered and demonstrated in the study was that MB-specific germline microsatellite variations mark those at risk for MB development and suggest that other mechanisms of cancer predisposition beyond heritable mutations exist for MB.

“This work is the first to demonstrate the ability of specific DNA sequences to differentiate children with cancer from their healthy counterparts,” added Dr. Rood.

Contributing Authors to this research study included:  Brian R. Rood, M.D., Harold R. Garner, Ph.D., Samuel Rivero-Hinojosa, Ph.D., and Nicholas Kinney, Ph.D.

proton center

Johns Hopkins Proton Therapy Center opens in collaboration with Children’s National

proton center

The Center at Sibley offers state-of-the-art, pencil beam proton therapy equipment, as well as next-generation imaging technologies such as dual energy CT-guided treatment that reduces the range of error, and the latest innovation in biomatrix magnetic resonance imaging designed to target moving tumors in organs like the lung and liver.

Pediatric cancer patients in the Greater Washington region now have access to one of the most advanced, lifesaving proton therapy technologies offered in the U.S. The Johns Hopkins Proton Therapy Center opened Oct.28, 2019, at Sibley Memorial Hospital in collaboration with Children’s National Hospital.

The proton collaboration with Children’s National expands an existing collaboration between Children’s National and Johns Hopkins Medicine that established the pediatric radiation oncology program at Sibley, which treats a wide range of children’s cancer. Now, Sibley will offer the only proton center in the Washington D.C. region with a dedicated pediatric team, staff who are trained in pediatrics instead of adult providers who also treat children.

“This collaboration allows us to bring the latest technology to the region and offer the most advanced cancer treatment to help children live better lives,” says Kurt Newman, M.D., president and CEO at Children’s National. “As one of the Top 10 children’s hospitals in the nation, our goal is to ensure that patients and families are receiving the best care possible.”

The Center at Sibley offers state-of-the-art, pencil beam proton therapy equipment, as well as next-generation imaging technologies such as dual energy CT-guided treatment that reduces the range of error, and the latest innovation in biomatrix magnetic resonance imaging designed to target moving tumors in organs like the lung and liver. A large mechanical arm called a gantry can move the beam 360 degrees around the patient, treating the tumor from several angles as it destroys tumor cells layer by layer.

“Proton therapy is an advanced technology that allows radiation to be delivered precisely to cancer tissue,” says Jeffrey Dome, M.D., Ph.D., vice president for Cancer and Blood Disorders at Children’s National. “This provides a significant advantage compared with conventional radiation therapy, especially in children, where sparing the healthy tissue that surrounds the tumor may be critical for normal growth and development. Proton therapy shows great promise to reduce long-term side effects of radiation treatment.”

The Center at Sibley will have a fully integrated research room, which will allow clinical, basic science and medical physics faculty to advance clinical trial research, translational research and technology development research in proton therapy. Leading experts and oncologists will study proton outcomes for sarcoma, gynecological tumors, pancreatic and liver tumors, lymph node cancers and tumors located near the heart and major blood vessels, such as lung or breast cancers. In addition, the researchers will examine how the proton energy that kills cancer cells interacts with non-cancerous cells and tissue surrounding the tumors.

The JJohns Hopkins Proton Therapy Center opens in phases. The first treatment room opened October 2019. The second room is scheduled to open in spring 2020, and the third room and fixed beam research room are scheduled to open in fall 2020.

Dr. Bornhorst talks with her patient Maddox Gibson,

A melanoma drug shows promise for NF1 plexiforms

Dr. Bornhorst talks with her patient Maddox Gibson,

Dr. Bornhorst talks with her patient Maddox Gibson, who is part of the compassionate use trial of selumentinib for which she serves as site principal investigator.

A class of drugs originally approved for stopping tumor growth in adult cancers including melanoma and small cell lung cancer may be the key to treating plexiform neurofibromas in neurofibromatosis type 1 (NF1), too. If effective, doctors will finally have a treatment to offer for children with complicated plexiform neurofibromas that can’t be removed via surgery.

These drugs, including selumentinib, work by inhibiting the activity of the mitogen-activated protein kinase enzymes MEK1 and MEK2. The enzymes have a direct impact on the activity of the cellular signaling pathway MAPK/ERK, which can be overactive some cancers.

Ongoing pre-clinical studies made possible by national and international neurofibromatosis research collaborations demonstrated that this same pathway is overactive in children with NF1 who have plexiform neurofibromas. The compelling findings from these studies set the stage for clinical trials to test the safety and efficacy of selumetinib and other MEK inhibitors as a therapy for pediatric NF1 patients with inoperable plexiform neurofibromas.

At Children’s National, these studies are run by clinicians such as Miriam Bornhorst, M.D., clinical director of the Gilbert Family Neurofibromatosis Institute and Aerang Kim, M.D., Ph.D. Children’s is one of only four sites in the United States to participate in a National Institutes of Health-led clinical trial to study the use of selumetinib in NF1. Dr. Kim is the site principal investigator and Dr. Bornhorst serves as co-principal investigator on phase 2 of the trial.

“Any time we find a medication that works with NF1, we’re excited, especially because for so many years, we didn’t have any of these options for these families,” Dr. Bornhorst says. “We’re offering something these families have never had before – a treatment that may stop growth and maybe even keep these tumors from returning. It means we’re doing more than managing symptoms – we’re really treating them.”

NF1 affects a relatively small number of people, particularly children. However, researchers and clinicians who are dedicated to the condition have banded together via collaborations and consortia to fuel research and development of new therapies across multiple institutions in the U.S. and abroad.

“Patients come to see me who’ve been at our clinic for years and I’ll talk about MEK inhibitors, and they are just shocked to hear there may be a new option,” Dr. Bornhorst says.

The NIH trial continues to collect data at four U.S. centers, with the ultimate goal of submitting the results for FDA review. Additional data is also collected from patients who didn’t qualify for the trial but who received the drug for compassionate use, an effort led by Dr. Bornhorst. The information collected from that compassionate use trial also helps investigators make the case to broaden the eligibility criteria for future trials.

“The medications are showing that they work,” Dr. Bornhorst notes. “Now we need to determine how to identify the patients who we know will need these therapies.”

To meet that need, other studies, led by both Dr. Bornhorst and Dr. Kim, seek radiographic and blood biomarkers that will identify children with NF1 who are more likely to develop plexiform neurofibromas, and whose plexiforms may progress to something malignant.

Test tube with DNA

“Liquid biopsies” could track diffuse midline gliomas

Test tube with DNA

A multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of diffuse midline gliomas could reliably predict the tumors’ response to radiotherapy.

Diffuse midline gliomas are rare, diagnosed in fewer than 800 Americans every year, the majority of whom are children. These cancers arise in the cellular “glue” that holds the brain and spinal cord’s neurons together, grow swiftly and have no cure. About half of patients with these cancers, including diffuse intrinsic pontine glioma, die within one year of diagnosis.

Clinical trials are increasingly investigating new treatments that could offer hope for patients and their families. Yet, thus far, there have been few ways to track the progression of these conditions, offering little insight on whether a treatment is hitting its intended goal.

To solve this problem, a multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of these cancers could reliably predict the tumors’ response to radiotherapy. The scientists published their results online Oct. 15, 2018, in Clinical Cancer Research.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The team at Children’s National searches for the histone 3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M,” says Lindsay B. Kilburn, M.D., a neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers children to not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients who had undergone a tumor biopsy.”

With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously, Nazarian adds.

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D., and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital;  John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Mathew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Oncology at Children’s National

Oncology at Children's National
ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

The immune system is the ultimate yin and yang, explains Anthony D. Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National in Washington, D.C. With an ineffective immune system, infections such as the flu or diarrheal illness can run unchecked, causing devastating destruction. But on the other hand, excess immune activity leads to autoimmune diseases, such as lupus or multiple sclerosis. Thus, the immune system has “checks and balances” to stay controlled.

Cancer takes advantage of “the checks and balances,” harnessing the natural brakes that the immune system puts in place to avoid overactivity. As the cancer advances, molecular signals from tumor cells themselves turn on these natural checkpoints, allowing cancers to evade immune attack.

Several years ago, a breakthrough in pharmaceutical science led to a new class of drugs called checkpoint inhibitors. These medicines take those proverbial brakes off the immune system, allowing it to vigorously attack malignancies. However, Dr. Sandler says, these drugs have not worked uniformly and in some cancers, they barely work at all against the cancer.

One of these non-responders is high risk neuroblastoma, a common solid tumor found outside the skull in children. About 800 U.S. children are diagnosed with this cancer every year. And kids who have the high-risk form of neuroblastoma have poor prognoses, regardless of which treatments doctors use.

However, new research could lead to promising ways to fight high-risk neuroblastoma by enabling the immune system to recognize these tumors and spark an immune response. Dr. Sandler and colleagues recently reported on these results in the Jan. 29, 2018, PLOS Medicine using an experimental model of the disease.

The researchers created this model by injecting the preclinical models with cancer cells from an experimental version of neuroblastoma. The researchers then waited several days for the tumors to grow. Samples of these tumors showed that they expressed a protein on their cell surfaces known as PD-L1, a protein that is also expressed in many other types of human cancers to evade immune system detection.

To thwart this protective feature, the researchers made a cancer vaccine by removing cells from the experimental model’s tumors and selectively turning off a gene known as Id2. Then, they irradiated them, a treatment that made these cells visible to the immune system but blocked the cells from dividing to avoid new tumors from developing.

They delivered these cells back to the experimental models, along with two different checkpoint inhibitor drugs – antibodies for proteins known as CLTA-4 and PD-L1 – over the course of three treatments, delivered every three days. Although most checkpoint inhibitors are administered over months to years, this treatment was short-term for the experimental models, Dr. Sandler explains. The preclinical models were completely finished with cancer treatment after just three doses.

Over the next few weeks, the researchers witnessed an astounding turnaround: While experimental models that hadn’t received any treatment uniformly died within 20 days, those that received the combined vaccine and checkpoint inhibitors were all cured of their disease. Furthermore, when the researchers challenged these preclinical models with new cancer cells six months later, no new tumors developed. In essence, Dr. Sandler says, the preclinical models had become immune to neuroblastoma.

Further studies on human patient tumors suggest that this could prove to be a promising treatment for children with high-risk neuroblastoma. The patient samples examined show that while tumors with a low risk profile are typically infiltrated with numerous immune cells, tumors that are high-risk are generally barren of immune cells. That means they’re unlikely to respond to checkpoint inhibiting drugs alone, which require a significant immune presence in the tumor microenvironment. However, Dr. Sandler says, activating an immune response with a custom-made vaccine from tumor cells could spur the immune response necessary to make these stubborn cancers respond to checkpoint inhibitors.

Dr. Sandler cautions that the exact vaccine treatment used in the study won’t be feasible for people. The protocol to make the tumor cells immunogenic is cumbersome and may not be applicable to gene targeting in human patients. However, he and his team are currently working on developing more feasible methods for crafting cancer vaccines for kids. They also have discovered a new immune checkpoint molecule that could make this approach even more effective.

“By letting immune cells do all the work we may eventually be able to provide hope for patients where there was little before,” Dr. Sandler says.

In addition to Dr. Sandler, study co-authors include Priya Srinivasan, Xiaofang Wu, Mousumi Basu and Christopher Rossi, all of the Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), at Children’s National in Washington, D.C.

Financial support for research described in this post was provided by the EVAN Foundation, the Catherine Blair foundation, the Michael Sandler Research Fund and SZI.

ID-KD vaccine induced T-cell cytotoxicity

Mechanism of Id2kd Neuro2a vaccination combined with α-CTLA-4 and α-PD-L1 immunotherapy in a neuroblastoma model. During a vaccine priming phase, CTLA-4 blockade enhances activation and proliferation of T-cells that express programmed cell death 1 (PD1) and migrate to the tumor. Programmed cell death-ligand 1 (PD-L1) is up-regulated on the tumor cells, inducing adaptive resistance. Blocking PD-L1 allows for enhanced cytotoxic effector function of the CD8+ tumor-infiltrating lymphocytes. Artist: Olivia Abbate

T cell

Clinical Trial Spotlight: Is more really better? Dose escalation of multi-antigen targeted T cells to illicit a more robust response

T cell

As the promise of immunotherapy in treating patients with cancer becomes more evident, physician researchers at Children’s National are pushing the needle further along. Holly Meany, M.D., is leading a Phase 1 dose-escalation trial to determine the safety and efficacy of administering rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA CTL) to patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or traditional therapy for a high-risk solid tumor due to the presence of refractory, relapsed and/or residual detectable disease.

“In the escalation portion of our trial, we found that the highest dose evaluated did not have unfavorable toxicity in these patients and is our recommended dose,” Dr. Meany said. “Our next step is an expansion of the trial in five distinct disease categories – Wilms tumor, neuroblastoma, rhabdomyosarcoma, adenocarcinoma and esophageal carcinoma – to examine efficacy on a broader level at the recommended dose.”

Dr. Meany and fellow research clinicians at Children’s National will evaluate not only what happens to the patients when given the additional dosage, but also what happens to the cells – How long will they last? Will they remain targeted against the same antigens or will they shift to target other proteins?

This novel trial is currently enrolling patients at Children’s National Health System in Washington, D.C.

  • PI: Holly Meany, M.D.
  • Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors (REST)
  • Status: Currently enrolling

For more information about this trial, contact:

Holly Meany, M.D.
202-476-5697
hmeany@childrensnational.org 

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Eugene Hwang in an exam room

Clinical Trial Spotlight: Creating a super army to target CNS tumors

Eugene Hwang in an exam room

Following the noted success of CAR-T cells in treating leukemia, Eugene Hwang, M.D., and a team of physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors.

Following the noted success of CAR-T cells in treating leukemia, physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors. Employing a strategy of “supertraining” the cells to target and attack three tumor targets as opposed to just one, Eugene Hwang, M.D., and the team at Children’s are optimistic about using this immunotherapy technique on a patient population that hasn’t previously seen much promise for treatment or cure. The therapy is built on the backbone of T cell technology championed by Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research, which is only available at Children’s National. Hwang sees this trial as an exciting start to using T cells to recognize resistant brain cancer. “We have never before been able to pick out markers on brain cancer and use the immune system to help us attack the cancer cells. This strategy promises to help us find treatments that are better at killing cancer and lessening side effects,” he says.

This Phase 1 dose-escalation is designed to determine the safety and feasibility of rapidly generated tumor multiantigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) or recurrent, progressive or refractory non-brainstem CNS malignancies. Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or surviving) will be enrolled in one of two groups: Group A includes patients with newly diagnosed DIPGs who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from a patient’s peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase 1 dose-escalation study. Group A patients: TAA-T will be infused any time >2 weeks after completion of radiotherapy. Group B patients: TAA-T will be infused any time >2 after completing the most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

For more information about this trial, contact:

Eugene Hwang, M.D.
202-476-5046
ehwang@childrensnational.org

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Karun-Sharma-and-kids-MR-HIFU

Clinical Trial Spotlight: Treating tumors with ThermoDox® and MR-HIFU

Karun Sharma, M.D., is working with AeRang Kim, M.D., Ph.D., to evaluate the use of ThermoDox®, a heat-activated chemotherapy drug, in combination with noninvasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) to treat refractory or relapsed solid tumors in children and young adults.

A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults.

This study is looking to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lyso-thermosensitive liposomal doxorubicin (LTLD), a heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, administered in combination with magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) in children with relapsed/refractory solid tumors.

MR-HIFU is an innovative device that provides precise and controlled delivery of heat inside a tumor using an external applicator. Unlike other heating systems used in local therapy, MR-HIFU is entirely non-invasive and does not use any radiation. Integration of MR imaging allows for real-time temperature monitoring for accurate and precise targeting of tumors. LTLD is a novel formulation of doxorubicin with the unique property of heat-activated release. This selective drug delivery mechanism allows for local and rapid release of doxorubicin in high concentrations in tumors when heated. This novel combination may potentiate known effective therapy to improve local control and drug delivery without increasing toxicity.

Children’s National Health System and Celsion Corp, a leading oncology drug-development company, were the first to launch a clinical study in the U.S. that evaluates the use of ThermoDox® with MR-HIFU. Learn more about the clinical trial.

For more information about this trial or other trials available at Children’s National, contact:

Melissa Salerno
Clinical Research Program Manager
202-476-2142
msalerno@childrensnational.org

View more open phase 1 and phase 2 cancer clinical trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Javad Nazarian

Meeting of the minds: Children’s National hosts first DIPG Round Table Discussion

Javad Nazarian at DIPG Round Table Discussion

Spearheaded by Javad Nazarian, Ph.D., MSC, Scientific Director of the Children’s National Brain Tumor Institute, the focused DIPG Round Table Discussion brought investigators, neurosurgeons and clinicians from North America, Europe and Australia to Children’s National in Washington, D.C.

Over 40 experts involved in the study and treatment of diffuse intrinsic pontine gliomas (DIPG) convened at the inaugural DIPG Round Table Discussion at Children’s National Health System Sept. 30-Oct. 2.

Spearheaded by Javad Nazarian, Ph.D., MSC, Scientific Director of the Children’s National Brain Tumor Institute, the focused DIPG Round Table Discussion brought investigators, neurosurgeons and clinicians from North America, Europe and Australia to Children’s National in Washington, D.C., to engage in dialogue and learn about the changing landscape of DIPG tumor biology and therapeutics. Attendees discussed the recent discoveries in DIPG research, precision medicine, preclinical modeling, immunotherapy, data sharing and the design of next generation clinical trials.

Families affected by DIPG also had an opportunity to participate in day 2 of the event. Many voiced the necessity of data sharing to ensure progress in the field. Dr. Nazarian seconded that point of view: “It is critical to get raw data and have it harmonized and integrated so that the end users (researchers) can utilize and do cross-data analysis…We need to break down the silos.” The highlight of the data sharing session was the Open DIPG Initiative that is spearheaded by Dr. Nazarian and the Children’s Brian Tumor Tissue Consortium (CBTTC).

Nazarian Lab at DIPG Roundtable Meeting

Eshini Panditharatna, Ph.D., Madhuri Kambhampati, Sridevi Yadavilli, M.D., Ph.D., and Erin Bonner of Children’s National at the DIPG Round Table.

As recent technological and molecular advances in DIPG biology have pushed the field forward, focus groups have become essential to share data, ideas and resources with the overarching goal of expediting effective treatments for children diagnosed with DIPG. An extremely aggressive form of pediatric brain cancer, DIPG accounts for roughly 10 to 15 percent of all brain tumors in children. Between 300 and 400 children in the United States are diagnosed with DIPG each year, but the 5-year survival for the brain tumor is less than 5 percent, a strikingly low number in comparison with other types of childhood cancer. DIPG research and clinical initiatives have changed in the past years mainly due to the generous support of families for basic research. The DIPG Open Table meeting was designed to coalesce a team of experts to expedite the first crack at curing this devastating childhood cancer.

Chima Oluigbo examines a patient

Eradicating epilepsy with Visualase

Chima Oluigbo examines a patient

Chima Oluigbo, M.D., and his team are using Visualase to identify and eliminate seizure foci and provide patients with a minimally invasive procedure for treating epilepsy.

About one in 26 people will be diagnosed with epilepsy in their lifetime. That adds up to about 3.4 million people in the U.S., or about 1 percent of the population nationwide. This condition can have huge consequences on quality of life, affecting whether children will learn well in school, eventually drive a car, hold down a job or even survive into adulthood.

For most of those that develop epilepsy, medications can keep seizures in check. However, for about a third of patients, this strategy doesn’t work, says Chima Oluigbo, M.D., an attending neurosurgeon at Children’s National Health System. That’s when he and his team offer a surgical fix.

Epilepsy surgery has come a long way, Dr. Oluigbo explains. When he first began practicing in the early 2000s, most surgeries were open, he says – they involved making a long incision in the scalp that can span half a foot or more. After drilling out a window of skull that can be as long as five inches, surgeons had to dig through healthy brain to find the abnormal tissue and remove it.

Each part of this “maximally invasive” procedure can be traumatic on a patient, Dr. Oluigbo says. That leads to significant pain after the procedure, extended hospital stays of at least a week followed by a long recovery. There are also significant risks for neurological complications including stroke, weakness, paralysis, speech problems and more.

However, open surgery isn’t the only option for epilepsy surgery anymore. Several new minimally invasive alternatives are now available to patients and the most promising, Dr. Oluigbo says, is called Visualase. He and his team are the only surgeons in the region who perform this procedure.

In Visualase surgeries, Dr. Oluigbo and his colleagues start by making a tiny incision, about 5 millimeters, on the scalp. Through this opening, they bore an even tinier hole into the skull and thread a needle inside that’s about 1.6 millimeters wide. “The brain barely notices that it’s there,” he says.

The tip of this wire holds a laser. Once this tip is placed directly at the seizure foci – the cluster of nerve cells responsible for generating a seizure – the patient is placed in an intraoperative magnetic resonance imaging (MRI) device. There, after checking the tip’s precise placement, the surgeons turn the laser on. Heat from the laser eradicates the foci, which the surgeons can see in real time using MRI thermography technology. The margins of the destroyed tissue are well-defined, largely sparing healthy tissue.

After the wire is removed, the incision is closed with a single stitch, and patients go home the next day. The majority of patients are seizure free, with rates as high as 90 percent for some types of epilepsy, Dr. Oluigbo says. Although seizure-free rates are also high for open procedures, he adds, Visualase spares them many of open surgeries’ painful and difficult consequences.

“Having done both open surgeries and Visualase,” Dr. Oluigbo says, “I can tell you the difference is night and day.”

Although open procedures will still be necessary for some patients with particularly large foci that are close to the surface, Dr. Oluigbo says that Visualase is ideal for treating medication-resistant cases in which the foci are buried deep within the brain. A typical example is a condition called hypothalamic hamartoma, in which tumors on the hypothalamus lead to gelastic seizures, an unusual seizure type characterized by uncontrollable laughing. He also uses Visualase for another condition called tuberous sclerosis, in which waxy growths called tubers develop in the brain, and for cancerous and benign brain tumors.

It’s gratifying to be able to help these children become seizure-free for the rest of their lives, says Dr. Oluigbo – even more so with the numerous updates he receives from families telling him how much this procedure has improved their children’s lifestyle.

“Visualase has completely changed the way that we approach these patients,” Dr. Oluigbo says. “It’s extraordinary to see the effects that this one procedure can have on the quality of life for patients here at Children’s National.”

Anthony Sandler

Anthony Sandler, M.D., Named Director of Sheikh Zayed Institute

Anthony Sandler

Children’s National Health System is pleased to announce that Anthony Sandler, M.D., current senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National, will now additionally assume the title of director, Sheikh Zayed Institute for Pediatric Surgical Innovation. He will succeed Peter Kim, M.D., the founding vice president of the Sheikh Zayed Institute, who is leaving to pursue other career opportunities after seven years at the helm of our surgical innovation center.

Dr. Sandler will be in a unique position, leading both in the research and clinical enterprises of Children’s National and will help to forge a stronger link between them, especially in the surgical subspecialties.

Internationally known for his work on childhood solid tumors and operative repair of congenital anomalies, Dr. Sandler is the Diane and Norman Bernstein Chair in Pediatric Surgery and is a professor of surgery and pediatrics at the George Washington University School of Medicine & Health Sciences. He is currently on the Board of Examiners for the Pediatric Surgery Qualifying Examination and has served on multiple committees for the American Pediatric Surgical Association and for the Children’s Oncology Group.

Dr. Sandler’s research interests focus on solid tumors of childhood and he’s presently studying tumor immunology and investigating immunotherapeutic vaccine strategies. He has co-developed a surgical polymer sealant that is R01 funded by the National Institutes of Health and is currently in pre-clinical trials. Dr. Sandler has over 120 peer-reviewed publications in clinical and scientific medical journals.

Analysis of a progressive diffuse intrinsic pontine glioma: a case report

rg_histological-dipg-image

What’s Known
Despite multiple clinical trials testing an assortment of new treatments, the survival rate for diffuse intrinsic pontine glioma (DIPG) remains abysmal, with most children succumbing to the pediatric brainstem tumor within 12 months of diagnosis. Focal radiation therapy, the primary treatment approach, has not improved overall survival. While the majority of DIPG tumors grow within the brainstem, metastases can occur elsewhere in the brain. Due to recent availability of tissue, new data are emerging about the biologic behavior of tumors, details that could be instrumental in constructing optimal treatment strategies.

What’s New
An otherwise healthy 9-year-old girl developed weakness in the left side of her face; magnetic resonance imagining revealed T2/FLAIR hyperintensity centered within and expanding the pons. Despite various treatments, her pontine lesion increased in size and new metastases were noted. The team led by Children’s National Health System researchers is the first to report comprehensive phenotypic analyses comparing multiple sites in primary and distant tumors. All tumor sites displayed positive staining for the H3K27M mutation, a mutation described in more than two-thirds of DIPGs that may portend a worse overall survival. Persistence of mutational status across multiple metastatic sites is particularly important since the effectiveness of some therapeutic approaches relies on this occurring. mRNA analyses, by contrast, identified a small number of genes in the primary tumor that differed from one metastatic tumor. This divergence implies that a single biopsy analysis for mRNA expression has the potential to be misleading.

Questions for Future Research
Q: Because a small cohort of genes in the girl’s primary tumor were different from genes in portions of the metastatic tumor, would genomic and proteomic analyses provide additional details about this genetic evolution?
Q: How do site-specific differences in mRNA expression affect decisions about which therapies to provide and in which order?

Source: Histological and Molecular Analysis of a Progressive Diffuse Intrinsic Pontine Glioma and Synchronous Metastatic Lesions: A Case Report.” J. Nazarian, G.E. Mason, C.Y. Ho, E. Panditharatna, M. Kambhampati, L.G. Vezina, R.J. Packer, and E.I. Hwang. Published by Oncotarget on June 14, 2016.

researcher using ice bucket in lab

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

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.

The role of NG2 proteoglycan in glioma

A large number of staffers contribute to the Children's National team effort to unravel the mysteries of DIPG. We photograph a few essential players in Dr. Nazarian's lab.

What’s Known
Neuron glia antigen-2 (NG2) is a protein expressed by many central nervous system cells during development and differentiation. NG2-expressing oligodendrocyte progenitor cells have been identified as the cells of origin in gliomas, tumors that arise from the brain’s gluey supportive tissue. What’s more, NG2 expression also has been associated with childhood diffuse intrinsic pontine glioma (DIPG) an aggressive tumor that accounts for 10 percent to 20 percent of pediatric central nervous system (CNS) tumors. Radiation can prolong survival by a few months, but children diagnosed with DIPG typically survive less than one year.

What’s New
Researchers are searching for appropriate targets and effective drugs that offer some chance of benefit. A team of Children’s National Health System researchers investigated whether NG2 – which plays a critical role in proliferation and development of new blood vessels and promotes tumor infiltration – could be a potential target for cancer treatment. Of the various options, antibody-mediated mechanisms of targeting NG2 are feasible, but the size of antibodies limits their ability to cross the blood-brain barrier. “Due to its role in maintaining a pluripotent pool of tumor cells, and its role in tumor migration and infiltration, NG2 provides multiple avenues for developing therapeutics,” the research team concludes. “Moreover, the large extracellular domain of NG2 provides an excellent antigen repertoire for immunotherapeutic interventions. As such, further research is warranted to define the role and expression regulation of NG2 in CNS cancers.”

Questions for Future Research

Q: Because healthy oligodendrocyte progenitor cells are important for the child’s developing brain, how could further characterization of NG2 isoforms help prevent drugs from damaging those beneficial cells?

Q: Could NG2-binding peptides cross the blood-brain barrier to deliver anti-cancer therapies precisely to tumor sites?

Source: The Role of NG2 Proteoglycan in Glioma.” S. Yadavilli, E.I. Hwang, R. J. Packer, and J. Nazarian. Published by Translational Oncology on February 2016.