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    MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA06.09 - Efficacy RENO Study Results of Oral Vinorelbine or Etoposide with Cisplatin & Chemo-Radiation in Stage III NSCLC. SLCG 10/02 (ID 4238)

      16:00 - 17:30  |  Author(s): C. Camps

      • Abstract
      • Presentation
      • Slides

      Background:
      This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation (oV) which has achieved comparable results as the IV formulation and patients (pts) prefer it.

      Methods:
      Pts between 18-75years, with histologically proven untreated and unresectable locally-advanced NSCLC (LA-NSCLC), adequate respiratory function, V20≤35% and ECOG-PS 0-1, were randomized 1:1 to oV-P arm: 2 induction cycles (cy) of oV-P followed by 2 cy more with RT; or to E-P arm: 2 cy of E-P concomitants to RT. Both arms with a total radiation dose of 66Gy administered 2 Gys daily. Primary endpoint was progression free survival (PFS) by RECIST 1.1. Secondary endpoints: overall response rate (ORR), overall survival (OS) and safety. With α-error of 0.05 (one-tailed test) and 0.1 β-error, median PFS unacceptable for the oV-P arm of 10 months (m) (p0) and a very acceptable of 15 m (p1), 122 eligible pts were required.

      Results:
      140 pts from 23 institutions of SLCG were randomized between 08/2011-12/2014. 134 pts were treated (66 in oV-P and 68 in E-P arms). Results based on this 134 pts are presented. Median age 62 years [39-76]; PS 0/1, 45%/55%; current smoker 51%; squamous cell 51%; stage IIIB 54%. 244 and 131 cy were given in the oV-P and E-P arms, respectively. All irradiated pts in oV-P arm received at least 60Gy, 7 pts in the E-P arm received less than 60Gy (4 due to toxicity). 1 pt (1.5%) in oV-P arm and 12 pts (17.6%) in E-P arm presented esophagitis G3/4 (p=0.002). 121 confirmed eligibility for efficacy analysis. ORR were 39 (64%) and 40 pts (67%) in the oV-P and E-P arms, respectively (p=0.889). After 16 m [1-43] of follow-up, 66% pts progressed and 43% pts died. Median PFS is 11.4 m (IC95%; 6-17) in oV-P arm and 11.8 m (IC95%; 7-16) in E-P arm (p=0.374).

      Conclusion:
      Both regimens achieve similar efficacy however oV-P has less toxicity, especially esophagitis G3/4. Further follow-up is needed for the survival analysis.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 2
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      P1.05-013 - Lung Tumorspheres as a Platform for Testing New Therapeutic Strategies in Non-Small Cell Lung Cancer (ID 4848)

      14:30 - 15:45  |  Author(s): C. Camps

      • Abstract

      Background:
      Resistance to treatment is one of the causes influencing the high mortality of lung cancer. This feature seems to be linked to a subpopulation known as Cancer Stem Cells (CSCs), which are able to grow as spheroids (suspension culture). The aim of the study was to obtain tumorspheres from lung cancer cell lines and to use them as an in vitro platform for drug screening.

      Methods:
      Cells from lung cancer cell lines (A549, H1650, PC9, H460 and H358) were grown in monolayer and as spheroids. Cultured cells were used: (i) to compare the cytotoxic effect of anticancer drugs in adherent vs lung-tumorspheres (ii) to perform a high-throughput screening with a commercial chemical library (Prestwick) and (iii) to analyze the citotoxicity of specific inhibitors of Wnt, Hedgehog and Notch pathways. Briefly, cells were plated at the desired density in 200 μl of medium in 96-well plates and compounds were added at 4 different concentrations (n=3). Cell viability was measured after 48 and 72h, using MTS Assay. Cell viability was normalized to the respective mock-treated control cells and presented as percentage of control.

      Results:
      Cells cultured in serum-free conditions were able to form spheroids, such as stem-like cells. Under these culture conditions, classical anticancer drugs (cisplatin, paclitaxel, vinorelbine and pemetrexed) exhibited mild or null cytotoxic effects on A549, H1650, PC9, H460 and H358 spheroids. Moreover, we performed a high-throughput screening with Prestwick library and remarkably, three compounds reduced the number of viable cancer cells. As regards ‘stemness’ inhibitors, Wnt (IWP2 and XAV939) and Hedgehog inhibitors (Vismodegib) show high activity against tumorspheres (p<0.05), suggesting them as possible therapeutic strategies in NSCLC

      Conclusion:
      Our data suggest that lung-tumorspheres showed resistance to classical anticancer drugs, strengthening its possible use as a short-term culture platform for a simple, and cost- effective screening to investigate novel therapeutic approaches. In this setting, some compounds were identified as promising therapeutic agents on lung tumorspheres, but confirmatory data are still necessary. This project was supported by [RD12/0036/0025] from RTICC, SEOM 2012, [PI12-02838 and PI15-00753] from ISCIII

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      P1.05-014 - Stemness Gene Expression Profile of Tumorspheres from Non-Small Cell Lung Cancer (ID 4748)

      14:30 - 15:45  |  Author(s): C. Camps

      • Abstract

      Background:
      Lung cancer features like chemoresistance, tumor progression or metastasis have consolidated lung cancer as the first cause of death cancer-related worldwide. Cancer stem cells (CSCs) are small subpopulations of stem-like cells that have been associated to these traits, constituting a promising target, but remaining largely unknown. In this study, we isolated CSCs from lung cancer cell lines and tumor tissue of resectable NSCLC patients using a sphere-forming assay and analyzed their gene expression profile.

      Methods:
      The investigation was carried out on cells from seven NSCLC tumor samples and six cell lines (H1650, H1993, H358, A549, PC9, H460) grown in monolayer and as spheroids. The expression of CSC-markers (CD133, EPCAM1, ALDH1A1, CD166, ABCG2, CD44, MUC1, BMI1, THY1), pluripotency promoters (KLF4, OCT4, NANOG, SOX2, MYC, CCND1), cell cycle regulators (CDKN1A, CDKN2A, MDM2, WEE1), invasiveness-related genes (CDH1, VIM, SNAI1, MMP2, MMP9, CEACAM5, ITGA2, ITGA6, ITGB1), Notch pathway (NOTCH1, NOTCH2, NOTCH3, JAG1, DLL1, DLL4, NUMB, HEY1, HES1), Wnt pathway (WNT1, WNT2, WNT3, WNT5A, CTNBB1, DKK1, FZD7) and Hedgehog pathway (SMO, PTCH1, SHH, GLI1) components were analyzed by quantitative real time PCR (RTqPCR). ACTB, CDKN1B and GUSB genes were used as housekeeping controls for the relative expression calculation.

      Results:
      Lungspheres showed significantly higher expression of the CSC-markers EPCAM1, CD44 and ALDH1A1 (p= 0.028, p= 0.021 and p= 0.043, respectively) and the quiescence promoter CDKN1A (p= 0.021) in comparison with their paired-monolayer cells. The epithelial to mesenquimal transition (EMT) inducer, SNAI1, as well as integrins ITGA2, ITGA6 and ITGB1 were overexpressed in tumorspheres (p= 0.011, p= 0.018, p= 0.016 and p= 0.013, respectively). Regarding the Notch signaling pathway, most ligands (JAG1 and DLL4) and receptors (NOTCH1 and NOTCH2) analyzed had increased expression in spheroids (p= 0.021, p= 0.028, p= 0.038 and p= 0.036, respectively). In Wnt pathway, we found higher expression levels of WNT3, CTNBB1 and GSK3B (p= 0.021, p= 0.008 and p= 0.021, respectively) in tumorspheres. No significant results were found for the rest of genes analyzed.

      Conclusion:
      Lung cancer spheroids from primary tumors and cell lines showed increased levels of genes related to CSCs properties. Genes belonging to Notch and Wnt signaling pathways were found to be more expressed in tumorspheres, suggesting that these pathways could be interesting lung-CSC targets. This work was supported in part, by grants RD12/0036/0025 from RTICC, and PI12-02838/PI15-0753 from ISCIII.