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Elisabeth Aliagas



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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Author(s): Elisabeth Aliagas

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)

      14:30 - 16:00  |  Presenting Author(s): Elisabeth Aliagas

      • Abstract
      • Presentation
      • Slides

      Background

      Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.

      Method

      MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.

      Result

      Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).

      Conclusion

      CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.

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