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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.

Yuan Zhu

The brain tumor field moves forward with new findings and a research grant

Yuan Zhu

Yuan Zhu, Ph.D., and other experts completed new research findings evaluating the effects of manipulating the growth-promoting signaling pathways in brain tumors associated with adults and children.

This month, experts at Children’s National Health System made great strides in brain tumor research, specifically in gliomas, glioblastomas and medulloblastomas. Led by Yuan Zhu, Ph.D., the scientific director and Gilbert Endowed Professor of the Gilbert Family Neurofibromatosis Institute and Center for Cancer and Immunology Research at Children’s National, the team completed new research findings evaluating the effects of manipulating the growth-promoting signaling pathways in brain tumors associated with adults and children. Dr. Zhu’s research was recently published in Cell Reports and he was also awarded a U.S. Department of Defense (DoD) grant to gain a better understanding of how low-grade gliomas form. Together, this work moves the needle on developing more effective treatments for these debilitating and life-threatening tumors.

The study

In his recently published paper, Dr. Zhu and his colleagues, including Drs. Seckin Akgul and Yinghua Li, studied glioblastomas, the most common brain tumor in adults, and medulloblastomas, the most common brain tumor found in children, in genetically engineered experimental models. Dr. Zhu found that when they removed the p53 gene (the most commonly mutated tumor suppressor gene in human cancers) in the experimental model’s brain, most developed malignant gliomas and glioblastomas, while Sonic Hedgehog (SHH)-subtype (SHH) medulloblastomas were also observed. They further suppressed the Rictor/mTorc2 molecular pathway that is known in the regulation of tumor growth. This action greatly reduced the incidence of malignant gliomas and extended the survival of the models, validating the concept that Rictor/mTorc2 could be a viable drug target for this lethal brain cancer in adults.

The study also found that the same Rictor/mTorc2 molecular pathway serves the opposite function in SHH medulloblastoma formation, acting as a tumor suppressor. Findings suggest that if the same drug treatment is used for treating SHH medulloblastoma in children, it could potentially have an adverse effect and promote growth of the tumors.

Ultimately, the study demonstrates that Rictor/mTORC2 has opposing functions in glioblastomas in adults and SHH medulloblastomas in children. While drug therapies targeting Rictor/mTORC2 may be successful in adults, the findings reveal the risks of treating children with pediatric brain tumors when using the same therapies.

The grant

Continuing the study of brain tumors, Dr. Zhu recently received a $575,000 grant from DoD to research benign gliomas, with the hope of gaining a greater understanding of how the tumors form. Low-grade gliomas, or benign brain tumors, are the most common brain tumors in children. While not lethal like their high-grade counterpart, these tumors can lead to significant neurological defects, permanently impacting a child’s quality of life. Most commonly, the tumor can impair vision, often leading to blindness.

Since the tumors only occur in children under the age of eight, Dr. Zhu believes they are linked to neural stem or progenitor cells that exist in the optic nerve only during development, or when children are under eight-years-old. To test if his hypothesis is correct, Dr. Zhu will develop a preclinical model that mimics human brain tumors to study the development of the optic nerve. If his theory proves correct, Dr. Zhu’s long-term goal is to develop a strategy that prevents the tumor formation from ever occurring, ultimately preventing vision loss in children. The grant begins in July and will run for three years.