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graphic abstract for brain tumor paper

First large-scale proteogenomic analysis offers insights into pediatric brain tumor biology

graphic abstract for brain tumor paper

In the first large-scale, multicenter study of its kind, researchers conducted comprehensive analysis yielding a more complete understanding of pediatric brain tumors (PBT), which are the leading cause of cancer-related deaths in children. Researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Children’s Brian Tumor Network (CBTN) generated and analyzed proteomic data, which identifies common biological characteristics among different tumor types. The consortia consist of collaborators from the Icahn School of Medicine at Mount Sinai, National Cancer Institute, Fred Hutchinson Cancer Research Center, Children’s National Hospital and Children’s Hospital of Philadelphia. The study, published in Cell on November 25, 2020, provides a clearer understanding of the molecular basis of pediatric brain tumors and proposes new therapeutic avenues.

The molecular characterization of brain tumors has largely hinged upon the presence of unique alterations in the tumor genome ignoring the many layers of regulation that exist between DNA and the functional biology of the tumor cell that is actuated by proteins. The integration of proteomic data identifies common biological themes that span histologic boundaries, suggesting that treatments used for one histologic type may be applied effectively to other tumors sharing similar proteomic features.

Brian Rood, M.D., medical director of the Brain Tumor Institute and associate professor of pediatrics in the Center for Cancer and Blood Disorders at Children’s National Hospital, participated in this study and explains the importance of what the team discovered.

Q: Why was it important that researchers came together to do this work?

A: Comprehensive characterization of the fundamental biology of pediatric brain tumors, including the proteogenomic analysis done in this study, is essential to better understand and treat pediatric brain tumors.

Our study is based on the recognition that proteomics and phosphoproteomics needs to be integrated with other omics data to gain an improved systems biology view of the molecular features of brain tumors. In addition, characterizing biological themes that cross histologic boundaries and cells of origin can suggest extending treatments shown to be effective in one type of tumor to other histologically disparate tumors sharing the same proteomic features.

Proteomic data further reveal the functional impacts of somatic mutations and copy number variations (CNVs) not evident in transcriptomic data alone. Further, kinase-substrate network analyses identify activated biological mechanisms of tumor biology.

This work was only possible because of a unique collaboration between the CPTAC program of the NCI and the CBTN, of which Children’s National is a member.

Q: How will this work advance understanding and treatment of pediatric brain tumors?

A: Pediatric brain tumors have not benefitted from molecularly targeted drugs as much as other tumor types largely because they harbor relatively few gene mutations. Therefore, identifying key pathways to target in these patients’ tumors has been a challenge. The integration of proteomic and phosphoproteomic data with genomic data allows for the construction of a more comprehensive model of brain tumor biology and nominates specific key pathways to be targeted.

Q: What did you find that excites you?

A: Proteomic data revealed a number of findings that were not present in the genomic data. We found evidence to support a molecularly targeted approach to treating craniopharyngioma, a tumor that has previously been unresponsive to chemotherapy. We also found a prognostic marker for high grade gliomas that do not have a mutation in the H3 histone. We were able to identify specific kinases that may dictate the aggressive nature of certain ependymoma tumors. Importantly, we demonstrated the potential of proteomic studies to uncover unique tumor biology, paving the way for more extensive investigations using this approach.

You can find the full study published in Cell. Learn more about the Brain Tumor Institute at Children’s National.

Brian Rood

Improving the understanding of medulloblastoma

Brian Rood

Brian Rood, M.D., employed quantitative proteomics to tumor samples that led to novel therapeutic targets for Medulloblastoma and other tumors.

In a recently published study, Brian Rood, M.D., a neuro-oncologist at Children’s National Health System, employed quantitative proteomics to tumor samples, a technique that could lead to novel therapeutic targets for medulloblastoma and other tumors in the future.

Currently, many experts use genomic characterization to understand the genetic makeup of cancer cells, which has deepened the field’s collective knowledge of tumor biology. However, it has remained challenging to infer specific information about how the tumors will respond and consequently develop more effective therapies. Medulloblastoma is the most common pediatric, malignant brain tumor. Through Dr. Rood’s research using proteomic analysis, he was able to identify and measure the protein makeup of medulloblastoma, which led to a potential pathway for clinical intervention to treat this life-threatening cancer. The findings were published online June 7, 2018, in Acta Neuropathologica Communications.

“The goal of this research was to find out how these tumor cells function at the protein level, which may ultimately help the field identify drug therapies to stop them,” says Dr. Rood. “The genes of a cancer cell are like a blueprint for a building, but the blueprints aren’t always followed in a cancer cell: Not every active gene will produce its corresponding protein. Proteins do the work of the cell, and understanding them will provide a better overall understanding of a cancer cell’s biology.”

Dr. Rood compared proteomic and genomic data to confirm that genetics do not accurately predict the quantity of proteins. By directly quantitating the proteins and comparing them between different subgroups of the disease, they were able to identify protein-based pathways driving tumor biology. With this information, Dr. Rood was able to demonstrate that medulloblastoma depends on a crucial pathway, the eukaryotic initiation factor 4F protein synthesis pathway, resulting in the identification of a potential target for new treatments in medulloblastoma.

Ultimately, Dr. Rood found that proteomic analysis complements genomic characterization and the two can be used together to create a more complete understanding of tumor biology. Going forward, he hopes proteomic analysis will become common practice for studying all tumors, allowing tumors to be categorized and grouped together by protein makeup to help the field identify more effective therapies for all tumors.