The Drivers of Oncogenesis of Brain Tumors: A Model for Precision Medicine

Research Seminar
Title: The Drivers of Oncogenesis of Brain Tumors: A Model for Precision Medicine
Speaker: Antonio Iavarone, M.D.
Professor, 
Department of Neurology and Department of Pathology, 
Institute for Cancer Genetics, 
Columbia University
Time: 13:00-14:30, May 11, 2018
Location: Youcai Deng Hall，School of Life Sciences
Host：Xiaodong Su
Abstract：
We are experiencing the exciting time of the genome era. For our work this means being able to contextualize the alterations of each genetic network in the natural environment of a specific tumor and identify the key driving modules on which specific tumor subgroups rely for growth, survival and progression. With this information in hand, we can target the critical alterations with specific drugs, often already available for other types of diseases. By focusing on one of the most lethal forms of human tumors, the glioblastoma multiforme (GBM), we have been able to make incredible progress along this line in the last two years. Our work in this area first discovered two transcription factors – Stat3 and C/EBP –that are responsible for activation and maintenance of the most aggressive gene expression signature of high-grade glioma, the mesenchymal signature. The therapeutic implication of this work has been our ability to efficient target the two transcription factors in preclinical mouse models with consequent collapse of the mesenchymal signature and extended survival [1]. More recently, we have identified the first examples of highly oncogenic and recurrent gene fusions in GBM, target their dependency in a particular tumor subtype, and observe dramatic anti-tumor effects. Recurrent gene fusions in GBM result in the constitutive activation of receptor tyrosine kinase genes (FGFR, EGFR and NTRK1) that render tumors addicted to the driver events [2, 3]. Among them, the FGFR-TACC gene fusion is the addicting oncogenic event with the highest therapeutic value. First, they are recurrent oncogenic events in several types of human cancer beside GBM (head & neck, lung, bladder, etc.). Second, FGFR-TACC fusions are potent oncogenes that transform normal cells by activation of non-canonical substrates and precipitation of aneuploidy. Finally, human tumors harboring FGFR-TACC fusions acquire marked sensitivity to FGFR inhibitory compounds. It is not surprising that this line of investigation has matured towards clinical trials [4]. The strongly addicting oncogenic activity of FGFR-TACC fusions is endowed in the unique, dual oncogenic mechanism implemented by these genetic events, which is summarized in Fig. 1. The FGFR-TACC fusion proteins aberrantly localizes on top of the spindle pole of mitotic cells. This results in mis-localization at a crucial site for the organization of mitosis of a constitutively active tyrosine kinase that ultimately perturbs mitotic progression and promotes chromosome mis-segregation and aneuploidy, a hallmark of malignant neoplasms. However, chromosome mis-segregation and aneuploidy per se would be associated with loss of cellular fitness but they are exploited for neoplastic transformation and maintenance by the strong non-canonical signaling events triggered by FGFR-TACC.
The integrated computational-experimental pipeline that we developed plus our ability to functionalize any genetic brain tumor module was recently applied to the entire landscape of CNVs, somatic mutations and gene fusions of human GBM. This information is quickly advancing our ability to translate each new genetic finding into the personalized context of the clinical setting.
References
1. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010,463:318-325.
2. Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 2013,45:1141-1149.
3. Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012,337:1231-1235.
4. Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, Marie Y, Bruno A, Boisselier B, Giry M, Savatovsky J, Touat M, Belaid H, Kamoun A, Idbaih A, Houiller C, Luo FR, Soria JC, Tabernero J, Eoli M, Paterra R, Yip S, Petrecca K, Chan JA, Finocchiaro G, Lasorella A, Sanson M, Iavarone A.
Clin Cancer Res. 2015 Jan 21. pii: clincanres.2199.2014.. 
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