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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.

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.

Marius George Linguraru

Marius George Linguraru, D.Phil., M.A., M.Sc., awarded Department of Defense grant for Neurofibromatosis application development

Marius George Linguraru

Marius George Linguraru, D.Phil., M.A., M.Sc., is a principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, where he founded and directs the Precision Medical Imaging Laboratory. He’s an expert in quantitative imaging and artificial intelligence.

Marius George Linguraru, D.Phil., M.A., M.Sc., a principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National has been awarded a Congressionally Directed Medical Research Program (CDMRP) grant through the Department of Defense. This grant allows Dr. Linguraru to develop a novel quantitative MRI application that can inform treatment decisions by accurately identifying which children with Neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG) are at risk of losing their vision.

This grant is part of the Neurofibromatosis Research Program of the CDMRP, which fills research gaps by funding high impact, high risk and high gain projects. Dr. Linguraru, who directs the Precision Medical Imaging Laboratory in the Sheikh Zayed Institute, is collaborating with the Gilbert Family Neurofibromatosis Institute and the Children’s Hospital of Philadelphia on this project.

An expert in quantitative imaging and artificial intelligence, Dr. Linguraru has published several peer-reviewed studies on NF1 and OPG, a tumor that develops in 20 percent of children with NF1. The OPG tumor can cause irreversible vision loss, leading to permanent disability in about 50 percent of children with the tumor. This project, titled “MRI Volumetrics for Risk Stratification of Vision Loss in Optic Pathway Gliomas Secondary to NF1” will provide doctors certainty when identifying which children with NF1-OPG will lose vision and when the vision loss will occur.

Dr. Linguraru and his team will validate the quantitative MRI application that they’re developing by studying children at 25 NF1 clinics from around the world. Doctors using the application, which will perform comprehensive measurements of the OPG tumor’s volume, shape and texture, will upload their patient’s MRI into Dr. Lingurau’s application. Using recent advances in quantitative image analysis and machine learning, the application will then definitively determine whether the child’s NF1-OPG is going to cause vision loss and therefore requires treatment.

This diagnosis can occur before visual acuity starts to decline, which provides an opportunity for early treatment in children at risk for vision loss. Dr. Linguraru believes that early diagnosis and treatment can help to avoid lifelong visual impairment for these patients while preventing unnecessary MRIs and aggressive chemotherapy in pediatric patients who are not at risk of vision loss.

Occurring in one in 3,000 to 4,000 live births, NF1 is a genetic condition that manifests in early childhood and is characterized by changes in skin coloring and the growth of tumors along nerves in the skin, brain and other parts of the body. It is unknown why the OPG tumor caused by NF1 only results in vision loss for 50 percent of children. Some children will sustain lifelong disability from their vision loss, despite receiving treatment for their tumor, likely because treatment was started late. In other instances, doctors are unknowingly treating NF1-OPGs that would never cause vision loss.

Dr. Linguraru and his team have already proven that their computer-based, quantitative imaging measures are more objective and reliable than the current clinical measures, enabling doctors to make earlier and more accurate diagnoses and develop optimal treatment plans.

Children's National employs 45 pediatric neurologists and 6 pediatric neurosurgeons.

2019 at a glance: Neuroscience at Children’s National

The Children’s National Division of Neurology and Neurosurgery is consistently recognized by U.S. News & World Report as one of the top neurology programs in the nation.
Roger Packer high fives patient Olivia Enos

Kids’ resilience pushes neurologist to seek better therapies

Roger Packer high fives patient Olivia Enos

“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 Health 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.

The full session at the Health Care Heroes event was featured in Crain’s Detroit Business.

2016 Neurobiology of Disease in Children Symposium: neurofibromatosis features Children’s National expert

Roger Packer, M.D., Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Gilbert Neurofibromatosis Institute at Children’s National Health System, was an invited speaker at the 2016 Neurobiology of Disease in Children Symposium: Neurofibromatosis (NF). This conference brought together experts from around the world to discuss the newest developments in the understanding and treatment of children with NF. While at the conference, which was held on October 26, 2016, Dr. Packer gave an update of the Department of Defense-sponsored Neurofibromatosis Clinical Trial Consortium. The Neurofibromatosis Clinical Trials Consortium, of which Dr. Packer is the group chair, was established by the Department of Defense Neurofibromatosis Research Program to develop and perform clinical trials for the treatment of NF complications in children and adults.

Read more about the symposium.