The history of successful targeted therapy of cancer largely coincides with the inactivation of recurrent and oncogenic gene fusions in hematological malignancies and recently in some types of epithelial cancer. Glioblastoma multiforme (GBM) is among the most lethal and incurable forms of human cancer and targeted therapies against common genetic alterations in GBM have not changed the dismal clinical outcome of the disease. We have recently identified FGFR-TACC gene fusions as the first example of highly oncogenic and recurrent gene fusions in GBM, targeted their dependency in a particular tumor subtype, and observed dramatic anti-tumor effects. This line of investigation has recently matured towards a clinical trial. The same gene fusions have recently been identified in several other tumor types, thus establishing FGFR-TACC fusions as one of the most frequent chromosomal translocations in human cancer. From a mechanistic standpoint, we have discovered the unexpected capacity of FGFR-TACC fusions to trigger aberrant segregation of chromosomes during mitosis, thus initiating chromosomal instability (CIN) and aneuploidy, two hallmarks of human cancer. However, we still have incomplete understanding of the full repertoire of the oncogenic activities of FGFR-TACC fusions and the extent to which FGFR-TACC fusions in human GBM trigger growth-promoting signals and aneuploidy. The central objective of this proposal is to decipher how mechanistically FGFR-TACC fusion proteins promote malignant transformation. Our central hypothesis is that the FGFR-TACC fusion protein, through an aberrant mislocalization of a constitutively active tyrosine kinase (FGFR) over the mitotic spindle pole, disrupts proper chromosome segregation in mitosis and that this novel function represents a critical event for brain tumor initiation. This primary activity of FGF-TACC fusions is likely to cooperate with other growth-promoting signaling functions that complement the reduced cellular fitness associated with loss of mitotic fidelity and aneuploidy, to induce full-blown-tumorigenesis. To identify the mechanistic determinants of brain tumor initiation and CIN instigated by FGFR-TACC fusions, this proposal will pursue three specific aims. In the first aim, we will identify the tyrosine phosphorylation landscape of substrates directly modified by the aberrant kinase activity of FGFR- TACC fusion proteins. In the second aim, we will determine the mechanism by which FGFR-TACC fusions disrupt proper chromosome segregation. In the third aim, we will model the CIN, growth promoting signaling functions and tumor initiating capacity of the FGFR3-TACC3 fusion in a conditional knock-in mouse strain that ex- presses the FGFR3-TACC3 protein in selected cells. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of FGFR-TACC fusions and lay the foundation for the optimization of the new therapeutic strategies that have been precipitated by the discovery of FGFR-TACC gene fusions in human cancer.
Chromosomal translocations leading to the generation of functional gene fusions create a state of oncogene addiction in the tumor cells harboring them and are the most desirable targets for the personalized therapy of cancer. We recently identified the first example of chromosomal translocations in malignant brain tumors that generate a fusion protein that dominantly induces chromosomal instability, a hallmark of human cancer and in this proposal we will identify the mechanism by which the FGFR-TACC fusion proteins cause chromosomal instability and initiate tumorigenesis in the brain. The therapeutic targeting of the mechanisms triggered by the new gene fusions will translate our genomic and experimental knowledge into highly specific cancer drugs that will personalize therapy and impact patient survival.
|Lee, Sang Bae; Frattini, Veronique; Bansal, Mukesh et al. (2016) An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529:172-7|
|Di Stefano, Anna Luisa; Fucci, Alessandra; Frattini, Veronique et al. (2015) Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Clin Cancer Res 21:3307-17|