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M. Gottfried



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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-023 - ER homeostasis and motility of NSCLC cell lines can be therapeutically targeted with combined Hsp90 and HDAC inhibitors. (ID 1042)

      09:30 - 09:30  |  Author(s): M. Gottfried

      • Abstract

      Background
      Lung cancer remains the most common cause of cancer-related death in the world for which novel systemic treatments are urgently needed. Protein homeostasis that regulates protein levels and their fold is critical for cancer cell proliferation and survival. A complex network of cellular organelles and signaling cascades is involved in control of protein homeostasis including endoplasmatic reticulum (ER). Thus, proteins in control of ER homeostasis are increasingly recognized as potential therapeutic targets. Molecular chaperone heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) play an important role in ER homeostasis. Previous studies demonstrate that Hsp90 and HDAC inhibitors are individually functional against lung cancer. In this work we suggested that combined Hsp90 and HDAC inhibitors may elevate ER stress thereby enhancing the anti non small lung cancer (NSCLC) activity.

      Methods
      NSCLC cell lines (A549, H1299, H460) were treated with 17-DMAG (Hsp90 inhibitor), PTACH (HDAC inhibitor) and both drugs simultaneously for 24 hours. Cells were harvested and analyzed for ER stress markers (Immunoblot), viability (WST1 assay), motility (Scratch assay), and death (Flow cytometer).

      Results
      Using an in vitro cell line model we demonstrated that 17-DMAG co-administration with PTACH caused elevated ER stress (more than 110%, p<0.05) accompanied by apoptotic cell death (Annexin V) (7-21%, p<0.05). Moreover, 17-DMAG/PTACH treated cells lost the ability to migrate (57-85% of scratch closure, p<0.05).

      Conclusion
      Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in lung cancer cell lines. Indeed, the elevated ER stress caused by 17-DMAG/PTACH combined treatment leads to increased cell death of NSCLC cell lines compared to the application of the drugs separately.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-020 - Bone marrow mesenchymal stem cells deleteriously affect lung cancer cell lines. (ID 1034)

      09:30 - 09:30  |  Author(s): M. Gottfried

      • Abstract

      Background
      Lung cancer remains the most common cause of cancer-related death in the world. The major advances in treatment of lung cancer have brought only minor improvements in survival; therefore novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Therefore, we decided to study the effect of bone marrow (BM) MSCs on non small cell lung cancer (NSCLC) cell lines. Recent studies indicate that translation initiation factors are over expressed in multiple cancers and negatively impact NSCLC prognosis. Interestingly, translation initiation is highly modulated by microenvironmental cues. Hence, special emphasis will be attributed to the role of translation initiation in the crosstalk between the malignant lung cells and the BM-MSCs.

      Methods
      Specifically, we will determine the influence of MSCs (co-culture) and MSCs conditioned media on the proliferation, viability, migration of NSCLC cell lines (A549, H1299, and H460). We will also explore the effect on translation initiation factors implicated in cancer progression (eIF4E, eIF4GI, DHX29).

      Results
      Preliminary results demonstrate that 48h co-culture of NSCLC cell lines with MSCs conditioned media significantly decreased cell number (A549: 60%, H1299: 50%, H460: 10%, p<0.05) and viability (A549: 70%, H1299: 50%, H460: 60%, p<0.01) yet had no effect on cell cycle or death. Moreover, MSCs conditioned media decreased NSCLC cells motility (H1299: 60%, H460: 70%, p<0.05) and attenuated eIF4GI expression and activity as indicated by the levels of its targets (H1299: peIF4G 65%, total eIF4G 40%, SMAD5 30%, cMyc 80%; H460: peIF4G 90%, SMAD5 85%, cMyc 40%, p<0.05).

      Conclusion
      Ongoing work in our lab is aimed at dissecting whether the effects are dependent on direct cell-cell contact or mediated by soluble factors. Results that indicate translation initiation is modulated by MSCs derived components will mark new therapeutic targets for lung cancer treatment.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-040 - Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomized, double-blind, placebo-controlled phase 3 study in second-line advanced non-small cell lung cancer (NSCLC) patients (ID 2812)

      09:30 - 09:30  |  Author(s): M. Gottfried

      • Abstract

      Background
      Nintedanib is an oral, twice-daily angiokinase inhibitor targeting VEGFR-1–3, PDGFR-α/β and FGFR-1–3. LUME-Lung 1 is a placebo-controlled phase III trial investigating nintedanib plus docetaxel in advanced NSCLC patients after failure of first-line chemotherapy.

      Methods
      Stage IIIB/IV or recurrent NSCLC patients were randomised to receive nintedanib 200 mg bid plus docetaxel 75 mg/m[2] q21d (n=655), or placebo plus docetaxel (n=659). The primary endpoint was centrally reviewed progression-free survival (PFS) analysed after 714 events; the key secondary endpoint was overall survival (OS) analysed hierarchically after 1121 events, first in adenocarcinoma patients and then all patients. Quality of Life (QoL) was included as a secondary endpoint. Lung cancer symptoms and health-related QoL were assessed every 21 days until the first follow-up visit using the EORTC (QLQ-C30/LC13) and EQ-5D questionnaires. Changes of ≥10 points as compared with baseline were considered clinically significant. Analyses of cough, dyspnoea and pain symptoms were prespecified. Time to deterioration (TTD, first 10-point worsening from baseline) was analysed using a stratified log-rank test. An exploratory analysis of all subscales/items from the EORTC QLQ-C30/LC13 questionnaires estimated the respective hazard ratios for TTD using a Cox proportional hazards model.

      Results
      LUME-Lung 1 showed that nintedanib in combination with docetaxel significantly prolonged PFS for all patients regardless of histology (3.4 vs 2.7 months; HR 0.79, 95% CI: 0.68–0.92; p=0.0019), with a trend for improved median OS (10.1 vs 9.1 months; HR 0.94, 95% CI: 0.83–1.05; p=0.272) and significantly improved OS in patients with adenocarcinoma (HR: 0.83; p=0.0359; median 10.3 to 12.6 months). The most common AEs were diarrhoea and reversible ALT elevations. With respect to the QoL assessment, there was a high compliance rate of >80% until treatment course 25 for QLQ-LC13 and QLQ-C30 in both treatment arms. The addition of nintedanib to docetaxel did not influence TTD for cough (HR 0.90; 95% CI: 0.77–1.05; p=0.1858), dyspnoea (HR 1.05; 95% CI: 0.91–1.20; p=0.5203) or pain (HR 0.95; 95% CI: 0.82–1.09; p=0.4373), and maintained global health status/QoL (HR 0.952; 95% CI: 0.83–1.10). There was a significant deterioration in scores for nausea and vomiting, appetite loss and diarrhoea. The results were similar for adenocarcinoma patients with respect to cough (HR 0.97; 95% CI: 0.78–1.20; p=0.7744), dyspnoea (HR 1.04; 95% CI: 0.86–1.26; p=0.6813) and pain (HR 0.93; 95% CI: 0.76–1.13; p=0.4785); however, there was a trend for improved global health status/QoL (HR 0.86; 95% CI: 0.71–1.05). For squamous cell carcinoma patients, there was a trend for delayed TTD for cough (HR 0.84; 95% CI: 0.66–1.07; p=0.1561) and a maintained global health status/QoL (HR 0.975; 95% CI: 0.788–1.206). Further analyses are ongoing and will be presented at the congress.

      Conclusion
      In second-line NSCLC patients, docetaxel plus nintedanib did not result in any significant improvements in cough, dyspnoea or pain compared with placebo and docetaxel. However, PFS was improved in patients of all histologies receiving docetaxel and nintedanib, and OS was improved in patients with adenocarcinoma histology without adversely affecting self-reported QoL.