• Room 03.008 - CCRCB Block 5 MBC Site

    United Kingdom

19992019
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Personal profile

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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  • 69 Similar Profiles
Colorectal Neoplasms Medicine & Life Sciences
Apoptosis Medicine & Life Sciences
Caspase 8 Medicine & Life Sciences
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Drug Therapy Medicine & Life Sciences
CASP8 and FADD-Like Apoptosis Regulating Protein Medicine & Life Sciences
Neoplasms Medicine & Life Sciences
irinotecan Medicine & Life Sciences

Network Recent external collaboration on country level. Dive into details by clicking on the dots.

Projects 2006 2019

Research Output 1999 2019

A Machine Learning Platform to Optimize the Translation of Personalized Network Models to the Clinic

Salvucci, M., Rahman, A., Resler, A. J., Udupi, G. M., McNamara, D. A., Kay, E. W., Laurent-Puig, P., Longley, D. B., Johnston, P. G., Lawler, M., Wilson, R., Salto-Tellez, M., Van Schaeybroeck, S., Rafferty, M., Gallagher, W. M., Rehm, M. & Prehn, J. H. M., 17 Apr 2019, In : JCO Clinical Cancer Informatics. 17 p.

Research output: Contribution to journalArticle

Open Access
File
Protein Array Analysis
Colorectal Neoplasms
Proteins
Immunohistochemistry
Workflow
Fusobacterium nucleatum
Meta-Analysis
Colorectal Neoplasms
Survival
Neoplasms

Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform

Matveeva, A., Fichtner, M., McAllister, K., McCann, C., Sturrock, M., Longley, D. B. & Prehn, J. H. M., 25 Sep 2019, In : PLoS Computational Biology. 15, 9, 22 p., e1007374.

Research output: Contribution to journalArticle

Open Access
File
caspase-8
Death Domain Receptors
Death Domain Receptor Signaling Adaptor Proteins
Caspase 8
Receptor

Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours

McDaid, W. J., Greene, M. K., Johnston, M. C., Pollheimer, E., Smyth, P., McLaughlin, K., Van Schaeybroeck, S., Straubinger, R. M., Longley, D. B. & Scott, C. J., 18 Oct 2019, In : Nanoscale. 13 p.

Research output: Contribution to journalArticle

Chemotherapy
Epidermal Growth Factor Receptor
Antibodies
Tumors
Nanoparticles

Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer

Dunne, P. D., Coleman, H. G., Bankhead, P., Alderdice, M., Gray, R. T., McQuaid, S., Bingham, V., Loughrey, M. B., James, J. A., McCorry, A. M. B., Gilmore, A., Holohan, C., Klingbiel, D., Tejpar, S., Johnston, P. G., McArt, D. G., Nicolantonio, F. D., Longley, D. B. & Lawler, M., 13 Feb 2018, In : Oncotarget. 9, 17, p. 13834-13847 14 p.

Research output: Contribution to journalArticle

Open Access
File
Adjuvant Chemotherapy
Colonic Neoplasms
Biomarkers
Recurrence
Neoplasms

Impact

Development and Commercialization of a Technology Platform to Enable Biomarker Discovery and Validation

Richard Kennedy (Participant), Paul Harkin (Participant), Patrick Johnston (Participant), Alison Hosey (Participant), Julia Miskelly (Participant), Margaret Murray (Participant), Jennifer Quinn (Participant), Colin James (Participant), Jude Mulligan (Participant), Peter Daly (Participant), Paul Mullan (Participant), Julie Mussen (Participant), Ultan McDermott (Participant), Richard Wilson (Participant), Daniel Longley (Participant)

Impact: Health Impact, Quality of Life Impact

Thesis

Characterisation of an acetylation-dependent FLIP/Ku70 complex that regulates FLIP expression

Author: Kerr, E. M., Jul 2012

Supervisor: Longley, D. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

File

The Role of c-FLIP in Regulating Resistance to Ionizing Radiation

Author: McLaughlin, K. A. J., Jul 2016

Supervisor: Longley, D. (Supervisor) & Prise, K. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

File