The Roles of Neutrophil Elastase in Lung Cancer
Recruitment status was: Recruiting
Lung cancer is the leading cause of cancer death in Hong Kong. Lung adenocarcinomas is the most common type, accounting for 70% of lung cancer and the molecular target of epidermal growth factor receptor (EGFR) gene mutation at exons 18 - 21 is present in about 50% of lung adenocarcinomas. The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) mutations are commonly present in the other 50% that are EGFR wildtype. EGFR and K-ras mutations are found to be mutually exclusive in the same tumor. EGFR-tyrosine kinase inhibitor (TKI) can be used as treatment for EGFR mutated tumors while no specific targeted therapy can be recommended for EGFR wildtype tumors and these patients often receive chemoirradiation, which is toxic and clinical response is suboptimal. There is a need to find alternative molecular pathways/targets in EGFR wildtype lung adenocarcinomas.
Even with EGFR mutations, good clinical response to EGFR-TKI is achieved in about 70% of these patients. This would mean suboptimal targeting of the EGFR gene or the presence of alternative pathways mediating tumor progression and susceptibility to therapy. Exploration of molecular pathways in lung cancer may allow for discovery of new molecular targets for therapeutic development.
Neutrophil infiltration is frequently observed in lung cancer. Recognized similarities between neutrophils and cancer cells include (i) ability to circulate as single cells; (ii) target attachment via vascular system; (iii) target invasion. The major difference is that migrated neutrophils will undergo apoptosis while cancer cells can escape apoptosis.
This led to the postulation that neutrophils and cancer cells may share similar inflammatory cascades by secreting a similar panel of proteases, and one of these could be neutrophil elastase (NE). Animal studies demonstrated that NE from neutrophils moves into lung tumor cells and mediates lung tumor growth via degradation of Insulin receptor substrate-1 (IRS-1), leading to activation of intracellular phosphoinositide-3-kinase (PI3k) and the v-akt murine thymoma viral oncogene homolog 1 (Akt) signaling pathways and the intracellular tyrosine kinase of the platelet-derived growth factor receptor (PDGFR).
The aims of this study are to demonstrate NE activities and the subsequent signaling cascades activated in lung cancer cells, and to verify NE and its related pathway activation in clinical lung cancer specimen.
This study will conclude the roles of NE and the therapeutic potential of NE/IRS-1/PI3K/PDGFR pathways in EGFR wildtype lung adenocarinomas.
Chronic Obstructive Pulmonary Diseases
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||The Roles of Neutrophil Elastase in Lung Cancer|
- The protein expression levels of biomarkers related to neutrophil elastase [ Time Frame: Jan 2011 - June 2013 (30 months) ] [ Designated as safety issue: No ]The protein expression levels of phosphorylated Akt (pAkt), IRS-1, IRS-2, PDGF, mitogen activated kinase(MAPK) as well as phosphorylated EGFR (pEGFR) and TNF-α and β-actin will be assessed semi-quantitatively on electrophoretic blotting intensity.
- Immunohistochemical staining for NE, IRS-1 and EGFR [ Time Frame: Jan 2011 - June 2013 (30 months) ] [ Designated as safety issue: No ]Fields captured from four different fields from each stained (NE, IRS-1 and EGFR) lung tumor slides will be scored as 0 = absent, 1 = weak, 2 = strong and present. In NE positive cases, concordant and discordant cases of IRS-1 vs PDGF or EGFR staining will be observed. Likelihood ratio tests determining if proportion of discordant cases was significantly larger than half the cases will be presented
Biospecimen Retention: Samples With DNA
|Study Start Date:||January 2011|
|Estimated Study Completion Date:||June 2013|
|Estimated Primary Completion Date:||June 2013 (Final data collection date for primary outcome measure)|
Lung Cancer group
Subject with histological confirmation of lung cancer
Subjects with no diagnosis of lung cancer
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT01360931
|Queen Mary Hospital|
|Hong Kong, Hong Kong, 0|
|Principal Investigator:||David CL LAM, MBBS, FRCP(Edin), FCCP, FACP||The University of Hong Kong|