BET bromodomain inhibitor (JQ1) and tumor angiogenesis

Abstract

Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …