Antonio Iavarone, MD
- Professor of Neurology
- Professor of Pathology and Cell Biology (in the Institute for Cancer Genetics)
The overarching theme of my 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 highâ€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 highâ€grade glioma. We now exploit Stat3 and C/EBP-beta as promising therapeutic targets in glioblastoma. 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 cancerâ€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 FGFRâ€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 FGFRâ€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 FGFRâ€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.
- Molecular genetics of tumors derived from the nervous system
THE HUWE1 UBIQUITIN LIGASE REGULATES MITOSIS, GENOMIC STABILITY AND ONCOGENESIS (Federal Gov)
Jul 1 2019 - Jun 30 2024
MECHANISMS OF ID2 REGULATION IN GLIOMA (Federal Gov)
Apr 1 2019 - Mar 31 2024
DISSECTING THE TUMOR MICROENVIRONMENT OF GLIOMA BY SINGLE CELL ANALYSIS (Private)
Apr 1 2020 - Mar 31 2022
LICENSE PATHWAY AGREEMENT (Private)
Dec 1 2017 - Nov 30 2021
DETERMINING THE MOLECULAR BASIS OF SCHWANNOMATOSIS THROUGH IDENTIFICATION OF LZTR1 SUBSTRATES (Private)
Jul 1 2019 - Jun 30 2020
IDENTIFICATION OF MECHANISMS OF RESISTANCE AND COMPOUNDS WITH DUAL INHIBITORY ACTIVITY AGAINST FGFRTACC FUSIONS (Private)
Jan 1 2018 - Dec 31 2019
CANCER CENTER SUPPORT GRANT (Federal Gov)
Jul 1 2014 - Jun 30 2019
(PQB5) RECONSTRUCTION OF EVOLUTIONARY NETWORKS USING CROSS-SECTIONAL GENOMIC DATA (Federal Gov)
Apr 1 2014 - Apr 30 2019
ESTABLISHING THE GENOMIC AND EPIGENOMIC LANDSCAPE OF SCHWANNOMATOSIS FOR BETTER UNDERSTANDING OF THE MECHANISMS OF DISEASE (Private)
Mar 1 2017 - Feb 28 2019
IDENTIFICATION AND MODELING OF DRIVER GENETIC MODULES IN GLIOBLASTOMA (Federal Gov)
Dec 10 2013 - Nov 30 2018
IDENTIFICATION, FUNCTIONAL CHARACTERIZATION AND THERAPEUTIC EXPLOITATION OF THE INTEGRATED LANDSCAPE OF GENETIC AND EPIGENETIC ALTERATIONS IN GLIOMA FROM PATIENTS WITH NF1 (Private)
Oct 1 2015 - Sep 30 2018
FUNCTIONAL ANALYSIS AND MODELING OF FGFR-TACC FUSION IN BRAIN CANCER (Private)
Mar 1 2017 - Feb 28 2018
IDENTIFICATION OF MECHANISMS OF RESISTANCE AND COMPOUNDS WITH DUAL INHIBITORY ACTIVITY AGAINST FGFR-TACC FUSIONS (Private)
Jan 1 2016 - Dec 31 2017
SYSTEMS BIOLOGY OF TUMOR PROGRESSION AND DRUG RESISTANCE (Federal Gov)
Jun 1 2012 - Apr 30 2017
EFFICACY STUDY OF TAS-120 IN PRIMARY GBM CELLS HARBORING FGFR-TACC FUSIONS (Private)
Nov 5 2015 - Nov 4 2016
IDENTIFICATION OF DRUG SENSITIVITY OF GRADE IV ASTROCYTC TUMOURS BASED ON GENETIC LESIONS (Private)
Jul 1 2014 - Jun 30 2016
THE ROLE OF CTNND2 INACTIVATION IN MESENCHYMAL GLIOBLASTOMA (Private)
Jul 1 2014 - Jun 30 2016
IDENTIFICATION OF CTNND2-ASSOCIATED TRANSFORMATION PATHWAYS IN MESENCHYMAL GLIOBLASTOMA USING INSERTIONAL MUTAGENESIS (Private)
Jan 1 2014 - Dec 31 2015
COMPUTATIONAL ANALYSIS OF HIGH-GRADE GLIOMAS (Federal Gov)
Sep 1 2009 - Aug 31 2015
THE ROLE OF ID PROTEINS IN TUMOR DEVELOPMENT AND ANGIOGENESIS IN THE BRAIN (Federal Gov)
Jun 1 2003 - Jul 31 2015
THE ROLE OF ID PROTEINS IN DEVELOPMENT AND CANCER OF THE NERVOUS SYSTEM (Private)
Jan 1 2007 - Jan 31 2015
FGFR COMPOUND AZD4547 IN VITRO AND IN VIVO EFFECTS ON GLIOBLASTOMA MULTIFORME (Private)
Oct 17 2013 - Oct 16 2014
THE UREB-1 UBIQUITIN LIGASE IN NEURAL STEM CELLS AND CANCER (Federal Gov)
Sep 1 2008 - Jul 31 2014
DEVELOPMENT OF PERSONALIZED ANTI-GLIOMA THERAPEUTICS AND ELUCIDATION OF MOLECULAR MECHANISMS OF ACTION (Private)
Jan 1 2012 - Dec 31 2013
MECHANISMS AND REGULATION OF POST-TRANSLATIONAL MODIFICATIONS OF ID PROTEINS (Federal Gov)
Dec 1 2007 - Nov 30 2013
IDENTIFICATION AND VALIDATION OF NEW GENETIC ALTERATIONS IN PEDIATRIC BRAIN TUMORS (Private)
Jun 1 2011 - Jul 30 2013
THE ROLE OF ID PROTEINS IN DEVELOPMENT AND CANCER OF THE NER VOUS SYSTEM (Private)
Jan 1 2007 - Dec 31 2012
SYSTEMS BIOLOGY OF TUMOR PROGRESSION AND DRUG-RESISTANCE (Federal Gov)
Sep 30 2009 - Aug 31 2012
INHIBITOR OF DIFFERENTIATION- 2 IN CELL CYCLE REGULATION AND CANCER (Federal Gov)
Sep 30 2006 - Jul 31 2012
THE HUWE1-N-MYC TRANSCRIPTIONAL NETWORK AS A NEW THERAPEUTIC TARGET IN MALIGNANT GLIOMA (Private)
Jan 1 2010 - Dec 31 2011
Lasorella A., Benezra R., Iavarone A. The Id proteins: master regulators of cancer stem cells and tumor aggressiveness Nature Reviews Cancer, February 2014.
Frattini V., Trifonov V., Chan J.M., Castano A., Lia M., Abate F., Keir S.T., Ji A.X., Zoppoli P., Niola F., Danussi C., Dolgalev I., Porrati P., Pellegatta S., Heguy A., Gupta G., Pisapia D.J., Canoll P., Bruce J.N., McLendon R.E., Yan H., Aldape K., Finocchiaro G., Mikkelsen T., Privé G.G., Bigner D.D., Lasorella A., Rabadan R., Iavarone A. The integrated landscape of driver genomic alterations in glioblastoma. Nature Genetics, 45:1141-1149, 2013 [see also Nat Genet. NEWS and VIEWS 2013;45:1105-7. Genomics informs glioblastoma biology. Nature Reviews Clinical Oncology RESEARCH HIGHLIGHTS. 10:547, 2013 Glioblastoma landscape revealed; Cancer Discovery RESEARCH WATCH. 3:OF19, 2013. Driver alterations in glioblastoma suggest new therapeutic targets; Nature Reviews Neurology NEWS and VIEWS. 9:612-613, 2013].
Danussi C., Akavia U.D., Niola F., Jovic A. , Lasorella A., Pe'er D., Iavarone A. RHPN2 Drives Mesenchymal Transformation in Malignant Glioma by Triggering RhoA Activation. Cancer Research, 73:5140-5150, 2013.
Niola F., Zhao X., Singh D., Sullivan R., Castano A., Verrico A., Zoppoli P., Friedmann-Morvinski D., Sulman E., Barrett L., Zhuang Y., Verma I., Benezra R., Aldape K., Iavarone A., Lasorella A. The Id-RAP1 axis is essential for glioma maintenance and residency of glioma cells in the perivascular niche. J. Clin. Invest., 123:405-417, 2013.
Singh D., Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A. Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma Science 337:1231-1235, 2012. [see also Nature Reviews Cancer (12: 585, 2012). RESEARCH HIGHLIGHTS “Glioblastoma: Transforming fusions induce aneuploidy”, Cancer Discovery (2: 761, 2012). RESEARCH WATCH “FGFR–TACC Fusion Proteins Are Oncogenic in Glioblastoma”, Nature Medicine (18: 1472, 2012). RESEARCH HIGHLIGHTS “Finding Fusions”, Science Signaling (5: ec238, 2012). EDITORS’ CHOICE “Oncogenic TACC-tics”, Nature Reviews Clinical Oncology (9: 550, 2012). RESEARCH HIGHLIGHT “Constitutive fusion-protein kinase activity identified in GBM”, SciBX: Science-Business eXchange 5(34); doi:10.1038/scibx.2012.893, Neurology Today (12: P 27, 2012). ARTICLE IN BRIEF “Two New Mutations Identified as Potential Therapeutic Targets for Glioblastoma Multiforme”, HemOnc Today (September 10, 2012). NEWS “Some cases of glioblastoma caused by two fused genes, The Wall Street Journal (July 26, 2012) BY RON WISLOW “Some Brain Tumors Are Linked to a Gene Defect”, NCI-The Cancer Genome Atlas (December 18, 2012) BY PRITTY PATEL JOSHI “Researchers use TCGA Glioblastoma data in the discovery of a novel fusion gene implicated in a subset of brain tumors”, NCI Cancer Bulletin 9(16) page 3, August 7, 2012 “Discovery of fused genes in brain cancer points to possible treatment”, Discover Magazine January/February 2013 THE 100 TOP SCIENCE STORIES OF 2012 “#40 Brain cancer traced back to fused genes” page 49.
Niola F, Zhao X, Singh D, Castano A, Sullivan R, Lauria M, Nam HS, Zhuang Y, Benezra R, Di Bernardo D, Iavarone A, Lasorella A. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat. Cell. Biol. 14:477-487, 2012 (see also News and Views Nat Cell Biol. 2012, 14:450-452, Research Highlights Nat Rev Mol Cell Biol. 2012 13:278).
Barrett LE, Granot Z, Coker C, Iavarone A, Hambardzumyan D, Holland EC, Nam HS, Benezra R. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 17;21(1):11-24, 2012.
Schreiber SL, Shamji AF, Clemons PA, Hon C, Koehler AN, Munoz B, Palmer M, Stern AM, Wagner BK, Powers S, Lowe SW, Guo X, Krasnitz A, Sawey ET, Sordella R, Stein L, Trotman LC, Califano A, Dalla-Favera R, Ferrando A, Iavarone A, Pasqualucci L, Silva J, Stockwell BR, Hahn WC, Chin L, DePinho RA, Boehm JS, Gopal S, Huang A, Root DE, Weir BA, Gerhard DS, Zenklusen JC, Roth MG, White MA, Minna JD, MacMillan JB, Posner BA. Towards patient-based cancer therapeutics. Nat Biotechnol. 28:904-906, 2010.
Carro M.S., Lim W.K., Alvarez M.J., Bollo R.J., Zhao X., Snyder E.Y., Sulman E.P., Anne S.L., Doetsch F., Colman H., Lasorella A, Aldape K., Califano A, Iavarone A. A transcriptional module synergistically initiates and maintains mesenchymal transformation in the brain. Nature (Article), 463: 318-325, 2010 (see also Research Highlights, Network Spreading. Nature Reviews Cancer, 10:80-81, 2010).