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Title: Gene expression profiling of clinical response identifies novel biomarkers and therapeutic targets in lung and rectal cancers
Author: Petty, Russell D.
ISNI:       0000 0001 3486 2096
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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To improve and provide novel insights for the treatment of Non-Small Cell Lung Cancer (NSCLC) and rectal adenocarcinoma, an innovative approach using gene expression profiling has been used to identify key differences in the transcriptome between clinically responding and non-responding patients. Oligonucleotide microarrays were used to profile the expression of 22,283 transcripts in the NSCLC study (Aberdeen Microarray in Lung Cancer Study-1, AMLUCS1) and 54,675 transcripts in the rectal adenocarcinoma study (Aberdeen Microarray in Rectal Cancer Study-1, AMRECS1), and both studies represent the first of their type performed. In NSCLC, with bioinformatics analysis a set of 17 genes was identified whose expression was highly correlated with clinical response to platinum based chemotherapy (PtBC) and the ability of this ‘predictive gene set’ to correctly classify an independent set of patients for response was demonstrated.  Expression of the cross class lysosomal protease inhibitor Serpin B3 showed a highly significant  correlation with extent of clinical response (R= -0.978, p<0.0001) and was identified as an outlier (50 fold increase in non-responding versus responding NSCLCs).  Previous cell line studies had identified serpin B3 as inhibitor of cell death and a subsequent analysis of 1007 genes involved in the regulation of cell death identified other lysosomal protease inhibitors cystatin C and cystatin SN and provided evidence to support the common inhibition of classical apoptosis in NSCLC and hence an ‘apoptosis resistant phenotype’.  In an independent set of NSCLC patients it was demonstrated that protein expression of serpin B3 was significantly correlated with response and when combined with protein expression of cystatin C and its target protease cathespsin B was able to independently predict response to PtBC (OR 17.8, 95% C.I. 2.0-162.4, p=0.010).  These results identify the lysosomal protease inhibitors and the lysosomal cell death pathway as important determinants of clinical response in NSCLC.  These molecules and this pathway has not been hitherto suspected or investigated as a therapeutic target and in further investigations we demonstrated the therapy independent prognostic impact of serpin B3 protein expression in NSCLC, thereby implicating serpin B3 in disease pathogenesis. Contrasting prognostic impacts were found in lung adenocarcinomas (HR for death at 5 years = 0.43 (0.18-0.93, p=0.04)) and squamous cell carcinomas (HR for death at 5 years = 2.09 (1.03-4.72-0.93, p=0.03)).  Further investigations suggested that this may relate to an inhibitory role for serpin B3 in invasion and metastasis in squamous cell carcinoma but not adenocarcinoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available