PRESENTATION TITLE
Drivers and Classification of Brain Tumors: A Model for Precision Medicine

PRESENTER(S)
Antonio Iavarone, M.D.
Professor of Neurology and Pathology, Institute for Cancer Genetics, Columbia University, New York, NY

PRESENTER BIO

The overarching theme of our research program is the dissection of the role of proteins and networks (master regulators) that drive phenotypic states in normal and cancer cells of the brain. We use global and unbiased approaches to identify the genetic and transcriptional drivers of an obscure but incredibly important aberrant phenotype in brain tumors, the mesenchymal transformation of human high‐grade glioma. This phenotype endows one of the most lethal types of human cancer (the glioblastoma multiforme, GBM) with extremely aggressive features such as the ability to invade the normal brain and form new blood vessels.

In recent work we have identified and validated two transcription factors (Stat3 and C/EBP-beta) that, on their own, are necessary and sufficient to maintain the mesenchymal signature of high‐grade glioma.

The dissection of transcriptional networks has provided us with invaluable information on the nature of the master regulators that control whole signatures of gene expression. However, cancer is a genetic disease and we recognized that the reconstruction of transcriptional networks should be integrated with the development of systems approaches aimed at identifying novel cancer‐driving genetic alterations. The availability of massively parallel sequencing technologies has revolutionized the field of cancer genetics. By analyzing the whole transcriptome of human glioblastoma, we recently discovered that a subgroup of GBM patients is defined by the presence of gene fusions of FGFR and TACC genes in their tumors.

The identification of FGFR‐TACC fusions in GBM patients and the elucidation of the mechanistic consequences triggered by the fusion proteins for development of brain tumors have allowed us to translate these findings to preclinical models of the disease and design clinical trials in GBM patients harboring FGFR‐TACC fusions. This work provides the first example of an oncogenic and recurrent gene fusion in human GBM and leads our research towards the goal of personalized cancer translation.

Current areas of research include the mechanism of oncogenic transformation by FGFR‐TACC fusion proteins, validation and modeling novel glioblastoma gene fusions in the mouse and identification of novel driver genetic alterations relevant to the maintenance of phenotypically recognizable subtypes of brain tumors. A few examples of the recent work in the Iavarone’s laboratory are:

• the identification of the master regulators of the most aggressive subtype of GBM called the mesenchymal subgroup (Nature, 463: 318-325, 2010).
• The report of the first example of recurrent, oncogenic and addicting gene fusions in GBM (Science 337:1231-1235, 2012). These gene fusions are now being targeted with FGFR inhibitors in clinical trial enrolling GBM patients harboring FGFR-TACC fusions (Clin Cancer Res. 21:3307-3317, 2015).
• The development of experimental pipelines for the identification of driver genetic alterations in malignant brain tumors (Nature Genetics, 45:1141-1149, 2013).
• Leader of the Atlas-TCGA Analysis Working Group for pan-glioma (LGG and GBM, Cell, 164:550-563, 2016).
• The identification of the mechanism of oncogenic action of FGFR-TACC fusions in human cancer (Nature, 553:222-227, 2018).
• The landscape of molecular alterations of pediatric and adult glioma in patients with Neurofibromatosis type 1 (Nature Medicine, 176-187, 2019).
• A new single-cell based, multi-omics and functional classification of GBM with prognostic and therapeutic information (Nature Cancer, 2021, https://doi.org/10.1038/s43018-020-00159-4)

Antonio Iavarone, M.D.

12/90-8/94       Research Fellow, Molecular Oncology.  Brain Tumor, Research Center UCSF, San Francisco

9/94-8/98         Research Fellow, Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York

9/98-7/02         Active member, Comprehensive Cancer Center, Albert Einstein College of Medicine

9/98-1/02         Assistant Professor, Albert Einstein College of Medicine, Department of Developmental and Molecular Biology

9/98-1/02         Assistant Professor, Albert Einstein College of Medicine, Department of Neurology

1/02-7/02         Associate Professor, Albert Einstein College of Medicine, Department of Developmental and Molecular Biology

1/02-7/02         Associate Professor, Albert Einstein College of Medicine, Department of Neurology

7/02-5/2009     Associate Professor of Neurology and Pathology in the Institute for Cancer Genetics, Columbia University, New York

6/2009-Present   Professor of Neurology and Pathology and Cell Biology (with Tenure) in the Institute for Cancer Genetics, Columbia University, New York

Specialty and Present interest: Precision medicine, Brain tumors, chromosomal translocation, single cell sequencing, systems biology, systems pharmacology

VIEWING LOCATIONS
Zoom Link

LEARNING OBJECTIVES

• Demonstrate drivers and classification of brain tumors.
• Integrate drivers and classification of brain tumors.
• Classify drivers of brain tumors.
• Score drivers and classification of brain tumors.

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TRANSCRIPT
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