Tag Archive for: tumor

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

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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

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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.

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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.

Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape

Dr. Nazarian's lab

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What’s Known
Fewer than 150 U.S. children per year are diagnosed with diffuse intrinsic pontine glioma (DIPG), one of the most lethal pediatric central nervous system cancers. Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of these children die within two years of diagnosis. Molecular studies have yielded additional insight about DIPG, including that mutations in histone-encoding genes are associated with 70 percent of cases. Understanding mutations that drive tumors and the genomic landscape can help to guide development of targeted therapies.

What’s New: Frequently found genetic alterations prevalent in DIPGs

dipg-gene-mutations-and-biological-consequences

Source: “Clinicopathology of Diffuse Intrinsic Pontine Glioma and Its Redefined Genomic and Epigenomic Landscape.” E. Panditharatna, K. Yaeger, L.B. Kilburn, R.J. Packer, and J. Nazarian. Published by Cancer Genetics on May 1, 2015.