Tag Archive for: NF1

Cancer cells

DOD $1.3M award will launch clinical trial to treat sarcoma

Cancer cells

MPNST is a type of cancer called a sarcoma.

The Department of Defense (DOD) awarded Children’s National Hospital $1.3M to launch a unique clinical trial. The trial will evaluate the safety of a novel drug for patients with a rare but aggressive cancer known as malignant peripheral nerve sheath tumors (MPNST).

MPNST is a type of cancer called a sarcoma. While rare in the general population, about half of all MPNST are diagnosed in people with Neurofibromatosis Type 1 (NF1), a condition characterized by changes in skin coloring.

“MPNST is a life-threatening cancer for which there are no adequate medical options,” said AeRang Kim, M.D., Ph.D., director of clinical research of the Division of Oncology at Children’s National. “With the support of this grant, we will conduct a clinical trial to identify effective agents that could be of great benefit to all patients with NF1 who are at risk for sarcoma.”

MPNST are aggressive and frequently metastasize. The tumors that are not able to be removed with surgery rapidly progress and become lethal. In people with NF1, MPNST often develops within benign tumors, especially atypical benign tumors.

The hold-up in the field

Scientists have been looking at the cell signaling process within both pre-cancerous tumors and cancerous MPNST. Previous research has shown that the MEK and MDM2 signaling pathway influence the development and growth of these tumors. By blocking this interplay, the Zhu Laboratory at Children’s National has demonstrated that tumors can get smaller when treated with drugs that inhibit MEK and MDM2 in pre-clinical models.

What’s unique

The trial is uniquely designed to evaluate target inhibition of novel drugs by looking at signals that may help in determining tumor response. This work will provide people with NF1 and MPNST potentially helpful treatments and increase the knowledge for all people with NF1 and those at risk of MPNST. The drugs will be available to all patients who enroll to the study.

Miriam Bornhorst

Miriam Bornhorst, M.D., receives DOD New Investigator Award

Miriam Bornhorst

Miriam Bornhorst, M.D., clinical director of the Gilbert Neurofibromatosis Institute at Children’s National Hospital, received the Department of Defense’s Neurofibromatosis Research Program New Investigator Award.

This award, which is funded by the U.S. Department of Defense, has granted $450,000 in funds which Dr. Bornhorst hopes to use towards a study for patients with Neurofibromatosis Type 1 (NF1).

“There is very little known about metabolism in NF1, but we know that abnormalities in metabolism can not only affect a person’s overall health, but may also influence how tumors develop and grow,” Dr. Bornhorst explained.

Patients with NF1 can have defining clinical features related to growth and energy metabolism, such as short stature, low weight and decreased bone mineral density, findings that are more prominent in patients with high plexiform neurofibroma (a nerve sheath tumor) burden. The mechanism for this metabolic phenotype and its association with plexiform neurofibromas is not currently understood.

Preliminary data and the work of others suggest that the MAPK pathway may play a role in metabolism and Mek-inhibitor (MEKi) treatment, which decreases activity of the MAPK pathway and promotes weight gain in patients with NF1. Dr. Bornhorst’s study will be the first to explore global metabolism in NF1, determine which metabolic pathways are most active in plexiform neurofibromas and define how metabolomic signatures change during MEKi treatment.

“These findings will improve management and may lead to novel treatment options for patients with NF1,” she said. “It is my hope that the grant funding received for my study will not only allow me to generate data that will answer questions about metabolism in NF1, but foster interest in this topic so there are more opportunities for researchers in the future.”

The NFRP was initiated in 1996 to provide support for research of exceptional scientific merit that promotes the understanding, diagnosis, and treatment of neurofibromatosis (NF) including NF type 1 (NF1) and type 2 (NF2) and schwannomatosis. Since it was first offered, 346 new Investigator Award applications have been received and only 79 have been recommended for funding – with Children’s National receiving one in the latest grant cycle. The Gilbert Family Neurofibromatosis Institute at Children’s National is one of the world’s largest programs and the longest standing program in the United States.

Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

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. Linguraru’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.

How technology can predict vision loss in neurofibromatosis patients

Roger Packer and patient

For the first time, scientists have been able to definitively connect tumor volume and vision loss for children with neurofibromatosis type 1 (NF1). The first study to use quantitative imaging technology to accurately assess the total volume of individual optic nerve glioma (OPG) in NF1 was published in the November 4, 2016 issue of Neurology.

NF1 is a genetic condition that occurs in one in 3,500 births. Children with NF1 develop tumors in multiple locations across the nervous system. About 20 percent of children with NF1 will develop optic pathway gliomas, or tumors that occur in the visual system. Half of those with OPG will have irreversible vision loss, which occurs at a very young age, usually before age 3.

“Neuroradiologists typically assess these tumors through a measurement of the tumor’s radii using magnetic resonance images (MRI) of the patient,” said Marius George Linguraru, D.Phil., M.A., M.S., Principal Investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System, who is senior author on the study.

“These measurements aren’t detailed enough to serve as a good indicator of whether an OPG will cause vision loss for a child. Through automated computerized analysis, however, we’ve taken the MRI data and systematically analyzed the size and shape, as well as documented changes over time, all in 3-D, to pinpoint the volume of each tumor.”

A look inside the study

The study included children with NF1-related OPGs who are currently cared for at the Gilbert Family Neurofibromatosis Institute at Children’s National. Investigators compared the MRI analysis to the patients’ retinal nerve fiber layer (RNFL), a measure of the health of the visual system. The analysis showed a quantifiable negative relationship between increasing tumor volume within the structures of the anterior visual pathway (the optic nerve, chiasm, and tract) and decreasing thickness of the RNFL, indicating damage to the visual system and vision loss.

“Measuring the tumors in a precise, systematic manner, along with knowing how they grow, is the first step in recognizing which children are at highest risk for vision loss and to potentially identifying them before they suffer any visual symptoms,” added Dr. Linguraru. “If we know which children will probably lose vision, we can treat earlier, and perhaps improve how patients respond to treatment.”

A multicenter collaborative study to validate the findings will begin in 2017.