Daniel Longley

Professor

  • Room 03.008 - CCRCB

    United Kingdom

19992020

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Research Statement

My research is focussed on the extrinsic apoptotic pathway regulated by death receptors. In particular, my work investigates the predictive, prognostic and therapeutic relevance of the caspase 8 inhibitor FLIP and the inhibitor of apoptosis proteins (IAPs). We have shown that FLIP and IAPs are key regulators of death receptor-, chemotherapy- and radiation-induced apoptosis in a range of in vitro and in vivo cancer models. We are currently investigating ways in which FLIP can be targeted therapeutically.

The work of my group has indicated that FLIP and its partner protein procaspase-8 are frequently over-expressed together in many cancers, particularly those associated with inflammatory microenvironments, such as colorectal cancer, prostate cancer, non-small cell lung cancer and mesothelioma. High FLIP expression appears to be a potentially clinically useful biomarker for identifying patients most at risk of relapse and least likely to respond to standard chemotherapy. I also work on the development of predictive biomarkers for IAP-targeted therapeutics. 

Another element of my research is to investigate fundamental aspects of death receptor biology. We recently characterized the critical protein-protein interactions between FLIP and its key binding partners FADD and procaspase 8 that occur at complexes formed by death receptors following death ligand binding. The mechanism that we propose is a unique, paradigm-changing model that is likely to have implications for other multimeric procaspase activating platforms such as the apoptosome (caspase 9). We have also recently uncovered two novel aspects of FLIP biology that we are currently investigating: (1) FLIP’s regulation by the ubiquitination-proteasome system via cullin RING E3 ubiquitin ligases; and (2) the role of nuclear FLIP in regulating DNA damage responses. 

A major problem with current anti-cancer agents is their narrow therapeutic index. Working with Prof Chris Scott in the School of Pharmacy at Queen’s, we have developed tumour-targeted nanoparticle systems for delivery of anti-cancer drugs. This technology can reduce dose-limiting toxicities of a range of anti-cancer drugs, thereby widening their therapeutic windows. This technology also makes possible co-delivery of synergistic drug combinations and tumour-selective delivery of gold nanoparticles. As well as having novel radiotherapy and photothermic therapy applications, the gold nanoparticles, which we are developing with Prof Steven Bell (School of Chemistry), open up unique tumour imaging possibilities.

 

 

 

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