Virtual Library

Start Your Search

  • WCLC 2016

    17th World Conference on Lung Cancer

    Access to all presentations that occur during the 17th World Conference on Lung Cancer in Vienna, Austria

    Presentation Date(s):
    • Dec 4 - 7, 2016
    • Total Presentations: 2466

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

    Presentations will be available 24 hours after their live presentation time

Filter Results:

Show Only Available Presentations

  • +

    P1.02 - Poster Session with Presenters Present (ID 454)

    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
    • +

      P1.02-065 - Elucidating the Role of PIM Kinase and Its Therapeutic Potential in NSCLC (Now Available) (ID 4328)

      G. Moore, S. Heavey, C. Lightner, L. Brady, K. O’byrne, S.P. Finn, S. Cuffe, M. O'Neill, K. Gately

      • Abstract
      • Slides

      Background:
      PIM kinases are a family of three serine/threonine kinases: PIM1, PIM2 and PIM3 that have been shown to play a role in tumorigenesis. PIM1 is a downstream effector of oncoproteins ABL and JAK/STAT and regulator of BCL2/BAD and CXCR4. PIM activity is synergistic with the PI3K/Akt/mTOR pro-survival pathway and PIM2 has been shown to phosphorylate translational repressor 4E-BP1 and p70S6 independently of the PI3K pathway. Furthermore a synergism between PIM kinases and c-Myc has been reported. Here we investigate the expression of PIM1/PIM2/PIM3 in NSCLC cell lines and patient matched normal/tissue samples. The effect of a novel combined inhibitor of PI3K/mTOR/PIM kinases (IBL-301) on cell signalling, cell death and proliferation is also examined.

      Methods:
      PIM1/PIM2/PIM3 expression were examined by Western blot analyses in NSCLC cells (H1975 and H1838). Additionally, the frequencies of PIM1/PIM2/PIM3 expression in NSCLC patient tumour and matched normal adjacent samples (n=31) were investigated. The effectiveness of IBL-301 on cell signalling, cell viability and proliferation were examined by Western blot analysis, cell titre blue and BrdU assay respectively.

      Results:
      All three PIM isoforms were detected in the lung cancer cell lines tested. Similarly, all three PIM isoforms were expressed across the 31 NSCLC patient tumour and match normal adjacent tissue samples. To investigate this further PIM1 staining of FFPE tumour and match normal tissue from this cohort is currently underway. In two lung cancer cell lines, H1975 and H1838, IBL-301 was found to have a dose dependent effect on proliferation/viability with IC~50~ values in the nanomolar range. Additionally, western blot analyses have indicated that these novel drugs can suppress the phosphorylation of key players in cell signalling pathways linked to tumorigenesis including pAkt, p4E-BP1 and peIF4B.

      Conclusion:
      This is the first study to investigate the expression of all 3 isoforms of PIM in lung cancer specifically. All 3 isoforms were abundantly expressed across cells lines and patient tumour samples. Observed PIM expression in the immune cells of normal adjacent tissue may indicate a role in inflammation. This finding coupled with the promising in vitro data demonstrate the therapeutic potential of targeting PIM in NSCLC.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    P2.01 - Poster Session with Presenters Present (ID 461)

    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
    • +

      P2.01-031 - CCL Chemokines May Play an Important Role in Cisplatin Resistance (ID 4861)

      S. Ryan, P. Godwin, S. Heavey, K. Umezawa, M.P. Barr, S.G. Gray, B. Stanfill, A. Davies, S. Cuffe, S.P. Finn, D. Richard, K. Gately, K. O’byrne, A. Baird

      • Abstract

      Background:
      In the absence of a targetable mutation, cisplatin based chemotherapy is the backbone of NSCLC treatment. However, a diverse patient population combined with complex tumour heterogeneity is hampering its’ clinical utility. Although intrinsic and acquired resistance to cisplatin is common, the mechanisms have not yet been fully elucidated. However, some studies have suggested that inflammatory pathways may play a key role in chemo-resistance. The aim of this project is to increase our understanding of inflammatory mediated cisplatin resistance in NSCLC.

      Methods:
      A number of isogenic cell line models of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) cisplatin resistance were utilised to assess the role of inflammation in chemo-resistance. These included a sensitive parental cell line (PT) and a matched resistant subtype (CisR). The cell lines were screened for NFKB and a number of inflammatory mediators including chemokines and TLRs at the mRNA (RT-PCR/qPCR) and protein level (Western Blot/ELISA). A specific NFKB inhibitor, DHMEQ, and recombinant chemokines were employed to further characterise inflammatory pathways in PT and CisR cells in terms of cisplatin sensitivity, proliferation (BrdU ELISA), cellular viability (Cytell Cell Imaging System) and DNA damage response (Comet). An in vivo study was also completed using DHMEQ alone and in combination with cisplatin.

      Results:
      A number of NFKB targets and responsive pathways are deregulated in CisR cells compared with their matched sensitive PT cell line. Amongst others, CCL2 and CCL5 were altered across all NSCLC subtypes. Preliminary data suggests that DHMEQ enhances cisplatin sensitivity in both PT and CisR cells, conversely recombinant chemokines elicit a protective effect. Additionally, DHMEQ treatment resulted in opposite affects on CCL2 and CCL5 mRNA levels in the PT and CisR cell lines. This may reflect an alternative pathway hierarchy within the cells. Further characterisation is ongoing assessing chemokine specific inhibitors. Although, in vivo data suggests a trend of decreased tumour growth in the DHMEQ cohorts compared with vehicle control, the data was not significant. However, tumour samples appeared more necrotic with DHMEQ and are currently being characterised using IHC for necrosis and proliferation.

      Conclusion:
      Targeting chemokines downstream of NFKB may provide a means to overcome inflammatory mediated acquired and intrinsic NSCLC chemo-resistance. Given the increased significance of immuno-oncology agents to harness the body’s own immune system in the fight against cancer, these agents may also prove fruitful in re-sensitising patients to chemotherapy.

    • +

      P2.01-066 - PD-L1 Tumor Expression and Its Effect on Overall Survival among Patients with Resected Non-Small Cell Lung Cancer (NSCLC) (ID 6110)

      J.S.Y. Sui, M.Y. Teo, S. Rafee, J. Mc Fadden, K. Gately, M.P. Barr, S.G. Gray, S. Cuffe, S.P. Finn

      • Abstract

      Background:
      Anti-PD1 monoclonal antibodies have demonstrated survival advantage over conventional chemotherapy in progressive metastatic non-small cell lung cancer (NSCLC). The prognostic role of tumoral expression of PD-L1 in NSCLC remains conflicting. We performed this study to evaluate the impact of PD-L1 expression as a prognostic marker in non-metastatic NSCLC.

      Methods:
      NSCLC patients (pts) who underwent curative resection between 1998 and 2006 in St. James’s Hospital, Dublin were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumor specimens, arrayed on tissue microarrays (TMAs) with triplicate 0.6 mm cores. PD-L1 was scored as positive if membranous staining was present in >1% of tumor cells aggregated across the replicate cores to address heterogeneity. Clinical characteristics of the pts were obtained from the hospital electronic database including age, gender, histological subtype, smoking status, grade, tumor size, nodal status, stage and survival data.

      Results:
      One-hundred and forty-seven patients from our institutional database were included, of which 92 (63.0%) were males, with a median age of 65 years (range: 42-82). 53.1% (n=78) with squamous histological subtype, 43.5% (n=60) were ex-smoker and 50.3% (n=74) had Stage I disease. PD-L1 positivity vs negativity among non-smoker, ex-smoker and current smoker were 13.0% vs 20.9%, 47.8% vs 43.3% and 39.1% vs 35.8% respectively, (p=0.708). PD-L1 expression by IHC was significantly higher in squamous NSCLC compared to non-squamous NSCLC (34.7% vs 14.6%, p=0.030). We also noted increased PD-L1 positivity with rising tumor T stage (T1 vs T2 vs T3 vs T4: 7.1% vs 30.6% vs 0% vs 60%, p=0.023) and grade of differentiation (G1 vs G2 vs G3: 11.1% vs 19.6% vs 44%, p=0.039). There was no correlation between nodal status and PD-L1 expression (N0 vs N1 vs N2: 25.5% vs 25% vs 26.3%, p=0.995). PD-L1 expression appears to be independent of overall disease stage (I vs II vs III: 27.3% vs 22.7% vs 25.0%, p=0.921). The median overall survival for PD-L1 positive vs negative pts was 22.1 vs 20.8 months with HR of 0.64 (95% CI: 0.34-1.12, p=0.123). Overall survival rates of pts with PD-L1 positive vs negative tumors at 2 years were 47.8% vs 44.8% and at 5 years were 43.5% vs 26.9%.

      Conclusion:
      In our cohort, PD-L1 expression was not associated with poorer survival among resected NSCLC pts. Tumour size and grade of differentiation appear to correlate with PD-L1 expression which warrants further validation in future studies.

    • +

      P2.01-081 - CDCA3 is a Novel Prognostic Cell Cycle Protein and Target for Therapy in Non-Small Cell Lung Cancer (Now Available) (ID 5823)

      M.N. Adams, J. Burgess, K. Gately, C. Snell, D. Richard, K. O’byrne

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer-related mortality worldwide with a 5 year survival rate of 15%. Non-small cell lung cancer (NSCLC) is the most commonly diagnosed form of lung cancer. Cisplatin-based regimens are currently the most effective chemotherapy for NSCLC, however, chemoresistance poses a major therapeutic problem. New and reliable strategies are required to avoid drug resistance in NSCLC. Cell division cycle associated 3 (CDCA3) is a key regulator of the cell cycle. CDCA3 modulates this process by enabling cell entry into mitosis through degradation of the mitosis-inhibitory factor WEE1. CDCA3 itself is also degraded in G1 yet re-expressed in G2/M phase, to allow successful progression through the cell cycle. Herein, we describe CDCA3 as a novel prognostic factor in NSCLC and target to delay or prevent cisplatin resistance in NSCLC.

      Methods:
      CDCA3 expression was investigated in squamous and non-squamous NSCLC using several approaches including bioinformatic analysis of publicly available datasets, immunohistochemistry of a tissue microarray and western blot analysis of matched tumour and normal tissue and NSCLC cell lines. CDCA3 function in NSCLC was determined using several in vitro assays by siRNA depleting CDCA3 in a panel of three immortalized bronchial epithelial cell lines (HBEC) and seven NSCLC cell lines.

      Results:
      CDCA3 transcripts and protein levels are elevated in NSCLC patient tissue and highly expressed in tumour cells relative to proximal normal cells. High mRNA levels are associated with poor survival in resected NSCLC. Depletion of CDCA3 in vitro markedly impairs proliferation in seven NSCLC cell lines by inducing a mitotic cell cycle arrest, ultimately resulting in p21-dependent cellular senescence. Importantly, silencing of CDCA3 also greatly sensitises NSCLC cell lines to cisplatin. In line with these in vitro data, NSCLC patients that have elevated levels of CDCA3 and are treated with cisplatin have a poorer outcome than patients with reduced levels of the protein. To improve patient response to cisplatin, we are exploring novel strategies to suppress CDCA3 expression in tumour cells.

      Conclusion:
      Our data highlight CDCA3 as a novel factor in mediating NSCLC. We propose that evaluating novel strategies to target CDCA3 may prove a useful strategy is enhancing the anti-tumour activity of platinum-based chemotherapy and may ultimately benefit patient outcomes by preventing cisplatin resistance.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    P3.01 - Poster Session with Presenters Present (ID 469)

    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
    • +

      P3.01-064 - The Overexpression and Cleavage of SASH1 by Caspase-3 Stimulates Cell Death in Lung Cancer Cells (Now Available) (ID 5811)

      J. Burgess, E. Bolderson, S.G. Gray, M.P. Barr, K. Gately, S. Zhang, A. Baird, D. Richard, K. O’byrne

      • Abstract
      • Slides

      Background:
      SASH1 (SAM and SH3 domain-containing protein 1) is a recently identified gene with tumour suppressor properties and has a role in induction of apoptosis. Previous work has shown that 90 % of lung cancer cell lines have a decrease in SASH1 mRNA levels (Zeller et al., 2003), however little characterisation of SASH1 function in lung cancer has been undertaken.

      Methods:
      We evaluated SASH1 expression in transformed normal and malignant non-small cell lung cancer cell lines. We also utilised cell based assays to study the effects of altered SASH1 levels on cell survival and proliferation. Identification of a novel SASH1 targeting drug was performed through connectivity mapping.

      Results:
      SASH1 protein expression was down regulated in two of the five lung cancer cell lines compared to immortalized normal bronchial epithelial cells. Prognoscan assessment identified decreased SASH1 mRNA expression reduced patient survival. The depletion of SASH1 in lung cells resulted in a significant increase in cellular proliferation in cancer lung cells. Connectivity mapping predicted the drug Chloropyramine would lead to an increase in SASH1 expression. We demonstrated that Chloropyramine upregulates SASH1 in malignant cell lines. In keeping with this we have demonstrated the Chloropyramine inhibited lung cancer proliferation in vitro. We also explored the role of SASH1 in apoptosis. Following ultraviolet light exposure SASH1 is cleaved by Caspase-3. The C-terminal fragment of SASH1 then translocates from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild type SASH1 or cleaved SASH1 amino acids 231-1247 leads to an increase in apoptosis, however loss of the SASH1 cleavage site and/or nuclear translocation prevents this initiation of apoptosis. Mechanistically SASH1 cleavage is required for the translocation of the transcription factor NF-κB to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating a co-dependence between SASH1 and NF-κB for this process.

      Conclusion:
      We have shown that SASH1 contributes to apoptosis via a NF-κB-dependent mechanism. Agents that upregulate SASH1, such as chloropyramine or SASH1 gene therapy, are potential novel approaches to the management of NSCLC in the future.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.

  • +

    P3.02c - Poster Session with Presenters Present (ID 472)

    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      P3.02c-010 - Resistance Mechanisms to PI3K-mTOR Inhibition in NSCLC (Now Available) (ID 5355)

      G. Moore, S. Heavey, K. O’byrne, S.P. Finn, S. Cuffe, M. O'Neill, K. Gately

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality globally, having a 5 year survival rate of less than 15%. PI3K-mTOR signalling has been implicated in various hallmarks of cancer and this pathway is often dysregulated in NSCLC. Efforts to therapeutically target the PI3K-mTOR pathway have been hindered by emerging drug resistance. In this study, mechanisms of drug resistance were investigated in a H1975 cell line model of acquired resistance, following chronic exposure to a phase II PI3K-mTOR inhibitor (GDC-0980), Additionally, short term exposure of BEZ235 (another phase II PI3K-mTOR inhibitor) and IBL-301 (a novel PIM/PI3K/mTOR inhibitor) were investigated for effects on cell viability/proliferation and downstream signalling pathways.

      Methods:
      Alterations to the mRNA expression profile of GDC-0980 acquired resistant H1975 cells versus matched parent cells were examined using an 84-gene IL-6/STAT3 signalling-specific profiler array. Subsequently, selected genes were validated by qPCR. The effectiveness of BEZ235 and IBL-301 on cell viability of two lung cancer cell lines (H1975 and H1838) following 72 hour treatment were investigated by Cell Titre Blue. pAkt and p4E-BP1 expression were examined by Western blot analyses following treatment with BEZ235 and IBL-301 at 3, 6 and 24 hours.

      Results:
      Thirty candidate gene alterations were identified from the array profile and six genes were chosen for validation by qPCR (n=3). The pro-proliferative and pro-metabolic regulator mTOR and the anti-apoptotic protein BCL-2 were increased in GDC-0980 resistant cells (p<0.05 and p<0.001). Similarly, TNF-α and its receptor co-stimulatory molecule CD40 were increased (p<0.05 and p<0.01). Furthermore, the cell cycle inhibitor, CDKN1, and JAK-signalling blocker, SOCS1 were downregulated (both p<0.01) in GDC-0980 resistant cells. BEZ235 and IBL-301 had a dose-dependent effect on the viability of NSCLC cell lines with respective IC~50~ values of 9.42nM and 136.55nM in H1975 cells and 103.35nM and 159.27nM in H1838 cells. Treatments of 250nM BEZ235 or IBL-301 inhibited pAKt at all time points in the lung cancer cell lines. BEZ235 blocked translation repressor protein (p4E-BP1) across all 3 cell lines and time points while IBL-301 treatment resulted in a reduction in p4E-BP1 at 24 hours.

      Conclusion:
      This study highlights a number of genes involved in IL-6/STAT3 signalling that may contribute to PI3K-mTOR inhibitor resistance. BEZ235 and IBL-301 both decrease cell viability and inhibit PI3K pathway signalling and cap-dependent translation in NSCLC cell lines that warrant further investigation.

      IASLC Members: To view this content or have the option to purchase this event, click here to login.
      Conference Attendees & Access Code holders: Click here to enter your Access Code. Already entered your Access Code? Please login.