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R. Razzak



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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-011 - A prospective clinical study evaluating stage dependent sputum micro-RNA expression profiles for the detection of non-small cell lung cancer (ID 3440)

      09:30 - 09:30  |  Author(s): R. Razzak

      • Abstract

      Background
      Lung Cancer accounts for the greatest cancer related mortality worldwide. To date, no effective screening tool for Non-Small Cell Lung Cancer (NSCLC) exists. For patients with operable stage IA NSCLC, the 5-year survival can be as high as 80%. Early detection is crucial in improving long-term survival. MicroRNAs (miRNAs), a class of short noncoding RNA molecules. miRNA expression in biological fluid samples such as sputum has shown promise as a potential means of detecting NSCLC. Our objective was to utilize an efficient, cost-effective panel consisting of 3 miRNAs (miR-21, miR-210 and miR-372) for prospective validation as a potential means of accurately detecting NSCLC. This panel was selected based on retrospective analysis of 11 miRNAs our group had previously undertaken using separate NSCLC and control cohorts.

      Methods
      21 early NSCLC (≤ Stage II) patients, 22 advanced NSCLC (≥ Stage III) patients and 10 control subjects were prospectively accrued. A single sputum sample was obtained through spontaneous expectoration from each study participant. Detailed study participant and tumor characteristics were obtained. miR-21, miR-210 and miR-372 expression was conducted on each sputum sample and normalized to an endongenous control (U6) relative to a MRC-5 reference sample, using RNA reverse transcription and Quantitative real-time Polymerase Chain Reaction (RT-qPCR). Statistical evaluation consisted of unsupervised hierarchical cluster analysis of the experimental-normalized miRNA expression profiles using within-group linkage.

      Results
      The median ages of the early NSCLC cases, advanced NSCLC cases and controls were 68, 68 and 58.5 respectively. The majority of the early and advanced NSCLC patients had smoking histories (>90%). 60% of the controls had smoking histories. Mean tumor size (± standard deviation) for early and advanced NSCLC cases were 3.4 cm (± 2.1 cm) and 4.8 cm (± 1.7 cm) respectively. Adenocarcinoma and squamous cell carcinoma comprised 62% and 23.8% of early NSCLC cases. Adenocarcinoma and squamous cell carcinoma comprised 45.5% and 22.7% of advanced NSCLC cases. Comparing early NSCLC to controls, the use of miR-21, miR-210 and miR372 expression yielded a diagnostic sensitivity of 66.7% and a specificity of 90.0%. Advanced NSCLC patients had an improved sensitivity of 81.8% with the same specificity of 90.0%.

      Conclusion
      The utilization of miR-21, miR-210 and miR372 sputum expression might provide a sensitive and specific means of detecting NSCLC. The potential linkage between their expression and NSCLC stage may account for the higher sensitivity observed in the advanced NSCLC group. Future use of this promising panel on a larger population will be required to establish its potential application as a screening tool.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-007 - Epidermal Growth Factor Receptor Targeted Gold Nanoparticles for the Radiation Treatment of Non-Small Cell Lung Cancer (ID 1480)

      09:30 - 09:30  |  Author(s): R. Razzak

      • Abstract

      Background
      Lung cancer accounts for the greatest cancer related mortality world wide, with two thirds of all patients receiving radiation therapy as part of their cancer care. Despite advancements made, the overall 5-year survival in Canada remains less than 20%. Developments in nanotechnology have proven to possess exciting potential in the treatment of various malignancies. Nanoparticles with high atomic number, such as Gold (GNPs), facilitate surprising local enhancement secondary to gold’s strong photoelectric absorption coefficient. GNPs are capable of forming covalent bonds, enabling the creation of “targeted” radio-sensitizing agents. The goal of this study is to evaluate the in vitro and in vivo radiation potential and biodistribution profile of GNPs targeted against the epidermal growth factor receptor (EGFR) using the monoclonal antibody Cetuximab (GNP-cetuxumab) stabilized with thiolated polyethylene glycol (SH-PEG) for the treatment of non-small cell lung cancer (NSCLC). To date a comprehensive evaluation of such a platform has not been undertaken.

      Methods
      We examined the radiation enhancement of 50nm GNPs in vitro using SKMES-1 (High wild type EGFR expression) and h460 (low wild type EGFR expression) NSCLC cell lines, both possessing Kras mutations. MTS, clonogenic assays and flow cytometry were used to assess radiation effect using 4 groups (no GNPs, GNPs, GNPs bound to SH-PEG stabilizer, GNP-Cetuximab). In vivo biodistribution was conducted on balb-c nude mice bearing two flank subcutaneous SKMES-1 xenografts. One tumor received a single radiation exposure (200 kVp, 8 Gray) prior to tail vein injection of GNP-cetuximab or GNP-PEG in order to assess the effect radiation induced inflammation may have on GNP tumor uptake. Tumors and organs were harvested at various time points with GNP concentration determined using inductively coupled mass spectroscopy. In vivo radiation experiments were conducted on 3 flank tumor bearing groups (each group = 7): 1) radiation only, no nanoparticles 2) GNP-PEG, GNP stabilized by bound PEG and 3) GNP-Cetuximab. Four weekly radiation fractions (4Gy, 200 kVp) with weekly tail vein injection timing based on the biodistribution results were administered. Tumor growth kinetics was then evaluated.

      Results
      Significant in vitro radiation effect was observed in the GNP groups compared to the radiation only group. GNP-cetuximab and GNP-PEG demonstrated enhanced radiation effect as compared to unfunctionalized GNPs. In the biodistribution experiment, the peak intra-tumor concentration without pre-administered radiation in the GNP-PEG group was twice that of the GNP-Cetuximab group 5 days after tail vein injection. Tumor pre-irradiation resulted in a doubling of intra-tumor nanoparticle uptake in both groups. At the end of radiation therapy experiment, the GNP-PEG group demonstrated the greatest reduction in tumor growth as compared to the radiation alone group (52mm[3] vs 180mm[3 ]respectively, p<0.01).

      Conclusion
      Despite the superiority of GNPs bound to cetuximab in vitro as a radiation enhancer, the favorable tumor biodistribution of the GNP-PEG accounted for the most dramatically reduced tumor growth kinetics observed. The future utility of targeted nanoparticles requires further investigation in light of these findings. In this study we demonstrate the exciting in vitro and in vivo potential of GNPs in the radiation treatment of NSCLC.

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    P3.17 - Poster Session 3 - Bronchoscopy, Endoscopy (ID 185)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track:
    • Presentations: 1
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      P3.17-009 - A Prospective Clinical Study of MicroRNA Expression Profiling of Bronchoalveolar Lavage Fluids and Sputum as a Means to Distinguish Early Stage Non-Small Cell Lung Cancer Cases From Cancer-Free Controls (ID 3403)

      09:30 - 09:30  |  Author(s): R. Razzak

      • Abstract

      Background
      MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis and miRNA expression profiling is an emerging tool for the early detection of malignancy. We assessed the ability of microRNA (miRNA) expression profiling of bronchoalveolar lavage (BAL) fluids and sputum samples to distinguish early stage non-small cell lung cancer (NSCLC) cases from cancer-free controls.

      Methods
      The expression levels of 3 miRNAs (miR-21, miR-210, miR-372) were quantified in BAL fluids and sputum, normalized to an endongenous control (U6) relative to a MRC-5 reference sample, using RNA reverse transcription and Quantitative real-time Polymerase Chain Reaction (RT-qPCR). All sputum samples were collected by a single spontaneous expectoration while BAL fluids were obtained just prior to surgical resection. Unsupervised hierarchical cluster analysis was performed on the experimental-normalized miRNA expression profiles using within-group linkage and cosine correlation similarity.

      Results
      From April 2011 to January 2012, twenty-one eligible cases and 10 controls were entered into this study. The median age of cases was 70 years of which 17 were male and 4 were females. Thirteen cases had adenocarcinoma, five had squamous cell carcinoma, and 3 had large cell carcinoma. Twelve cases had stage I and 9 had stage II NSCLC. The median short axis diameter of the primary tumour amongst cases was 1.6 cm. With exception of one case, endobronchial lesions were not detected on inspection by flexible bronchoscopic examination prior to BAL fluid collection. The vast majority of cases were smokers (20/21). The median age of the control group was 58.5 and five were healthy without active medical conditions while five had COPD. Six controls had prior or current histories of smoking while 4 were never smokers. Cluster analysis of the miRNA expression profiles of BAL samples from 21 NSCLC cases and sputum samples from 10 cancer-free controls yielded a diagnostic sensitivity of 85.7% and specificity of 100%. Cluster analysis of sputum samples from the same 21 NSCLC cases and 10 cancer-free controls yielded a diagnostic sensitivity of 67.8% and specificity of 90%. A cosine similarity analysis of matched pairs of concordant and discordant BAL and Sputum samples was conducted and indicated that sampling error accounted for 6 of the 7 false negative results. This suggests that triplicate sputum sample collection could improve the overall sensitivity of this method for use as a safe, non-invasive screening test for NSCLC or as a pre-screening test to select patients for low-dose CT screening.

      Conclusion
      Hierarchical cluster analysis of 3 expressed miRNAs obtained from sputum and brochoalveolar lavage samples are highly specific and relatively sensitive methods for the timely diagnosis of early stage NSCLC. Larger, population-based studies are necessary for further validation of this promising approach in both the diagnostic and screening setting.