Tag Archive for: Yuan Zhu

Researchers hope to uncover puzzling mechanism of vision loss in kids with $2.7M DOD award

The Department of Defense Neurofibromatosis Research Program awarded Children’s National Hospital $2.7M to better understand a pediatric tumor as a blinding disease. The study design will specifically focus on targeting immune responses during the development of the tumor as a means to prevent or preserve vision before the tumor-associated irreversible neurological damage.

Why it matters

Nearly 20% of individuals with neurofibromatosis type 1 (NF1) develop tumors along the anterior visual pathway, involving optic nerves, optic chiasm and optic tracts, known as NF1-associated optic pathway gliomas (NF1-OPGs). This tumor is mainly diagnosed in children younger than seven years, which could lead to a lifelong disability.

NF1-OPGs often grow extensively along the optic pathway, and surgery is a high-risk treatment option. Consequently, human tumor tissues are rarely available for research.

Why we’re excited

“We are very excited about this research because, if successful, we will provide a strategy to treat patients with NF1-OPGs before visual impairment becomes irreversible,” said Yuan Zhu, Ph.D., scientific director and Gilbert Family Endowed professor at the Gilbert Family Neurofibromatosis Institute and senior investigator at the Center for Cancer and Immunology Research, both part of Children’s National. “We combine the expertise of glioma at the Children’s National and retinal biology at the NIH/NEI.”

The research will combine the synergistic expertise between Zhu on NF1 and OPG using pre-clinical models and Drs. Han-Yu Shih and Wei Li at the National Eye Institute of the National Institutes of Health (NIH/NEI) on retinal biology and immunology.

What’s unique

To shed light on the chemical signaling that occurs in the optical nerve with the presence of gliomas, the research approach will have three aims:

  • Isolate and characterize this abnormally infiltrating inflammatory cells and perform multi-omics experiments, including sophisticated genomic, epigenomic and transcriptomic assays, to study them during OPG initiation and progression.
  • Prevent or alleviate OPG-associated nerve damage, RGC death and vision loss.
  • Develop a novel model using the newly established genetic system to identify signals that induce inflammatory responses.
A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

Using targeted signaling pathway therapy to prevent pediatric glioma formation

Researchers at Children’s National Hospital identified a vulnerability in a developmental signaling pathway that can be hijacked to drive pediatric low-grade glioma (pLGG) formation, according to a pre-clinical study published in Developmental Cell. The study demonstrated that targeted treatment prevents tumor formation, long before irreversible damage to the optic nerve can cause permanent loss of vision. This finding will inform chemo-prevention therapeutic trials in the future.

Brain tumors are the most common solid tumors in children, the most prevalent of which are pLGGs. Approximately 10% to 15% of pLGGs arise in patients with the familial cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This is a genetic condition that increases risks of developing tumors along the nerves and in the brain.

Nearly 20% of children with NF1 develop pLGGs along the optic pathway, also known as NF1-associated optic pathway glioma (NF1-OPG). Despite many advances in cancer therapy, there are no definitive therapies available that prevent or alleviate the neurological deficits (i.e. vision loss) and that could improve the quality of life.

“The evidence presented can inform chemoprevention therapeutic trials for children with NF1-OPG,” said Yuan Zhu, Ph.D., scientific director and Gilbert Family Endowed professor at the Gilbert Family Neurofibromatosis Institute and associate director of the Center for Cancer and Immunology Research, both part of Children’s National. “This therapeutic strategy may also be applicable to children with the developmental disorders that are at high risk of developing pediatric tumors, such as other RASopathies.”

The mechanism of vulnerability to pLGGs during development is not fully understood. It has been implied that the cell population of origin for this debilitating tumor is transiently proliferative during development. The NF1 gene produces a protein that helps regulate normal cell proliferation, survival and differentiation by inhibiting MEK/ERK signaling. When there is loss of function in NF1, it abnormally activates the MEK/ERK signaling pathway and leads to tumor formation.

Certain cells that exist transiently during the normal development of the brain and optic nerve are vulnerable to tumor formation because they depend on the MEK/ERK signaling. In this study, researchers in Zhu’s lab identified cells that were MEK/ERK pathway dependent and grew during a transient developmental window as the lineage-of-origin for NF1-OPG in the optic nerve. The researchers used a genetically engineered pre-clinical model to design a transient, low-dose chemo-preventative strategy, which prevented these tumors entirely.

“When we provided a dose-dependent inhibition of MEK/ERK signaling, it rescued the emergence and increase of brain lipid binding protein-expressing (BLBP+) migrating GPs glial progenitors, preventing NF1-OPG formation,” wrote Jecrois et al. “Equally importantly, the degree of ERK inhibition required for preventing NF1-OPG formation also greatly improved the health and survival of the NF1-deficient model.”

Ongoing clinical trials using MEK inhibitors (MEKi) are being performed for children as young as 1 month old. Thus, it becomes increasingly feasible to design a chemo-preventative trial using a MEKi to treat children with NF1. These treatment paradigms may have the potential to not only prevent OPG formation, but also other NF1-associated and RASopathies-associated developmental defects and tumors.

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation. The middle panels highlighted by a red dashed box show an OPG in the optic nerve (arrows, top), exhibiting abnormal triply-labeled tumor cells, inflammation and nerve damage (the bottom three panels), which are absent in the normal (left panels) or MEKi-treated Nf1-deficient optic nerves (right panels). [Credit: Jecrois et al., Developmental Cell, (2021)]

Yuan Zhu

Yuan Zhu, Ph.D., receives Outstanding Scientist Award

Yuan Zhu

The George Washington University (GW) Cancer Center recently announced the selection of the 2021 GW Cancer Center Awards, recognizing excellence in research, mentorship and early career contributions.

The GW Cancer Center Outstanding Scientist Award was presented to Yuan Zhu, Ph.D., professor of pediatrics at the GW School of Medicine and Health Sciences (SMHS) and Children’s National Hospital. The award is presented to faculty members who make a noteworthy contribution in the areas of basic science, clinical science, translational science or population science.

In his nomination, Dr. Zhu was cited for his contributions to the understanding of the mechanisms underlying the development of tumors and altered brain development arising in the setting of the inherited condition neurofibromatosis type 1 (NF1). “Throughout his career, Dr. Zhu has had a remarkable consistency of focus in his scholarly work, where he has sought to advance new molecular and mechanistic insights to understand the biological basis of NF1 and the cancers arising in individuals affected by this genetic disease.”

You can find a full list of award winners here.

Research & Innovation Campus

Virginia Tech, Children’s National Hospital award $100,000 to fund collaborative cancer research pilot projects

Research & Innovation Campus

This pilot research program represents a growing academic research partnership between Children’s National and Virginia Tech. Last year, the two institutions announced that Virginia Tech will establish a biomedical research facility on the Children’s National Research & Innovation Campus.

Children’s National Hospital and Virginia Tech have awarded two $50,000 one-year pilot grants to multi-institutional teams of scientists for pediatric brain cancer research.

The inter-institutional program, which launched in December, promotes cross-disciplinary collaborations among researchers at both institutions. At Virginia Tech, the program is part of the Virginia Tech Cancer Research Alliance. Financial support for the program was provided by the Offices of the Physician-in-Chief and Chief Academic Officer at Children’s National, and by Virginia Tech’s Office of the Vice President for Health Sciences and Technology.

“We were delighted to see so many innovative and competitive research proposals for our first round of pilot grants in the area of brain cancer. By forging new research collaborations with our partners at Children’s National, we hope to make major strides in addressing one of the most common and devastating groups of cancers in children,” said Michael Friedlander, Virginia Tech’s vice president for health sciences and technology, and the executive director of the Fralin Biomedical Research Institute at VTC. “The pilot funding will bootstrap several programs to be able to acquire ongoing sustainable funding by providing the opportunity to test novel high impact ideas for new strategies for treating these disorders. There are simply too few good options for children in this space now and this partnership can change that for the better.”

The collaborative research initiative began through an agreement between the Fralin Biomedical Research Institute and the Children’s National Research Institute. The collaborative teams formed through a series of interactive discussions among Virginia Tech’s Cancer Research Alliance faculty members from the university’s Blacksburg and Roanoke campuses, and Children’s National’s neuro-oncology researchers.

“I am extremely excited by this collaboration between VT and CNH that is focused on pediatric brain tumors which is such an area of unmet need,” said Catherine Bollard, M.D., M.B.Ch.B.,, director of Children’s National’s Center for Cancer and Immunology Research. “I am confident that the funded proposals will soon advance our understanding of pediatric brain tumors and, more importantly, facilitate more joint efforts between two world-class institutions which is especially timely with the development of the Children’s National Research & Innovation Campus.”

Yanxin Pei, Ph.D., an assistant professor in the Center for Cancer Immunology Research at Children’s National, and Liwu Li, Ph.D., a professor of biological sciences in Virginia Tech’s College of Science, were awarded one of the pilot research grants to study how white blood cells called neutrophils are involved in metastatic MYC-driven medulloblastoma, an aggressive type of brain tumor in children that often resists conventional radiation and chemotherapies.

Yuan Zhu, Ph.D., the Gilbert Family Professor of Neurofibromatosis Research at Children’s National, and Susan Campbell, Ph.D., an assistant professor of animal and poultry sciences in Virginia Tech’s College of Agriculture and Life Sciences, were awarded funds to study glioma-induced seizures in mice with a genetic mutation that inhibits the production of P53, a key protein involved in suppressing cancer cell growth and division.

The successful applicants will receive funding starting this month and are expected to deliver preliminary data to support an extramural research application by 2024.

This pilot research program represents a growing academic research partnership between Children’s National and Virginia Tech. Last year, the two institutions announced that Virginia Tech will establish a biomedical research facility on the Children’s National Research & Innovation Campus. It will be the first research and innovation campus in the nation focused on pediatrics when it opens later this year and will house newly recruited teams of pediatric brain cancer researchers.

Liwu Li, Yanxin Pei, Susan Campbell, and Yuan Zhu

Liwu Li, Ph.D., Yanxin Pei, Ph.D., Susan Campbell, Ph.D., and Yuan Zhu, Ph.D., were awarded funding through the new pilot research program.

Yuan Zhu

Study suggests glioblastoma tumors originate far from resulting tumors

Yuan Zhu

“The more we continue to learn about glioblastoma,” Yuan Zhu, Ph.D., says, “the more hope we can give to these patients who currently have few effective options.”

A pre-clinical model of glioblastoma, an aggressive type of cancer that can occur in the brain, suggests that this recalcitrant cancer originates from a pool of stem cells that can be a significant distance away from the resulting tumors. The findings of a new study, led by Children’s National Hospital researchers and published July 22 in the journal Nature Communications, suggest new ways to fight this deadly disease.

Despite decades of research, glioblastoma remains the most common and lethal primary brain tumor in adults, with a median survival of only 15 months from diagnosis, says study leader Yuan Zhu, Ph.D., the scientific director and endowed professor of the Gilbert Family Neurofibromatosis Institute at Children’s National. Unlike many cancers, which start out as low-grade tumors that are more treatable when they’re caught at an early stage, most glioblastomas are almost universally discovered as high-grade and aggressive lesions that are difficult to treat with the currently available modalities, including surgery, radiation and chemotherapy.

“Once the patient has neurological symptoms like headache, nausea, and vomiting, the tumor is already at an end state, and disease progression is very rapid,” Dr. Zhu says. “We know that the earlier you catch and treat cancers, the better the prognosis will be. But here, there’s no way to catch the disease early.”

However, some recent research in glioblastoma patients shows that the subventricular zone (SVZ) – an area that serves as the largest source of stem cells in the adult brain – contains cells with cancer-driving mutations that are shared with tumors found in other often far-distant brain regions.

To see if the SVZ might be the source for glioblastoma tumors, Dr. Zhu and his colleagues worked with pre-clinical models that carried a single genetic glitch: a mutation in a gene known as p53 that typically suppresses tumors. Mutations in p53 are known to be involved in glioblastoma and many other forms of cancer.

Using genetic tests and an approach akin to those used to study evolution, the researchers traced the cells that spurred both kinds of tumors back to the SVZ. Although both single and multiple tumors had spontaneously acquired mutations in a gene called Pten, another type of tumor suppressor, precursor cells for the single tumors appeared to acquire this mutation before they left the SVZ, while precursor cells for the multiple tumors developed this mutation after they left the stem cell niche. When the researchers genetically altered the animals to shut down the molecular pathway that loss of Pten activates, it didn’t stop cancer cells from forming. However, rather than migrate to distal areas of the brain, these malignant cells remained in the SVZ.

Dr. Zhu notes that these findings could help explain why glioblastoma is so difficult to identify the early precursor lesions and treat. This work may offer potential new options for attacking this cancer. If new glioblastoma tumors are seeded by cells from a repository in the SVZ, he explains, attacking those tumors won’t be enough to eradicate the cancer. Instead, new treatments might focus on this stem cell niche as target for treatment or even a zone for surveillance to prevent glioblastoma from developing in the first place.

Another option might be to silence the Pten-suppressed pathway through drugs, a strategy that’s currently being explored in various clinical trials. Although these agents haven’t shown yet that they can stop or reverse glioblastomas, they might be used to contain cancers in the SVZ as this strategy did in the pre-clinical model — a single location that might be easier to attack than tumors in multiple locations.

“The more we continue to learn about glioblastoma,” Dr. Zhu says, “the more hope we can give to these patients who currently have few effective options.”

Other Children’s National researchers who contributed to this study include Yinghua Li, Ph.D., Wei Li, Ph.D., Yuan Wang, Ph.D., Seckin Akgul, Ph.D., Daniel M. Treisman, Ph.D., Brianna R. Pierce, B.S., Cheng-Ying Ho, M.D. /Ph.D.

This work is supported by grants from the National Institutes of Health (2P01 CA085878-10A1, 1R01 NS053900 and R35CA197701).