Murphy, Adrian G.

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Murphy, Adrian G.
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Murphy, Adrian G.

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  • Publication
    Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer
    (Nature Publishing Group, 2016-10-14)
    Murphy, Adrian G. 
    ;
    Casey, Rory 
    ;
    Maguire, Aoife 
    ;
    Butler, Clare T. 
    ;
    Conroy, Emer 
    ;
    Reynolds, Alison 
    ;
    Gallagher, William M. 
    ;
    Kennedy, Breandán 
    ;
    et al. 
    Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
      420Scopus© Citations 15
  • Publication
    Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer
    (Frontiers Media, 2016-09-21)
    Burke, Lorraine 
    ;
    Butler, Clare T. 
    ;
    Murphy, Adrian G. 
    ;
    Moran, Bruce 
    ;
    Gallagher, William M. 
    ;
    O'Sullivan, Jacintha 
    ;
    Kennedy, Breandán 
    Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF, and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore, CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.
      449Scopus© Citations 38