Author of

• 20154

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  P1.05 - Early Stage NSCLC (ID 691)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Early Stage NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24605

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    P1.05-022b - Identifying Novel Markers of Early Stage Lung Cancer Using a CRISPR/Cas9 Mouse Model (ID 9549)

    09:30 - 16:00  |  Presenting Author(s): Paola A Marignani
    • Abstract

    Background:
    In NSCLC, loss-of-function (LOF) mutations are found in tumour suppressors, highlighting the importance of these genes in the aetiology of lung cancer. The major tumour suppressors (TS) associated with the development of lung cancer are p53 and the kinase LKB1. Unlike oncogenes that have been successfully exploited therapeutically, LOF alterations in TS are difficult to exploit therapeutically. The goal of our research is to understand how the loss of TS function allows for metabolic and epigenetic adaptation that favour conditions for tumour growth.
    
    Method:
    We developed a CRISPR/Cas9 mouse model of lung cancer representative of tumour suppressors lost in NSCLC that has allowed for temporal evaluation of tumourigenesis. Here, we evaluated the role metabolism, epigenetics and the immune system plays in promoting tumour growth. Since LKB1 and p53 are the most common LOF tumour suppressors found in NSCLC, and KRas is the most commonly abundant of oncogene, using the Cre-dependent Cas9 mouse model developed by the Zhang Lab at the Broad Institute, mice were treated by inhalation with CRISPR-directed viruses that target the excision of Lkb1, p53 and activation of KRas compared to mice treated with control virus. Post-treatment, lungs were analyzed for metabolic, immunologic and epigenetic profiles.
    
    Result:
    Lung tumours were harvested from mice, followed by analysis of global epigenetic modifications, immunological markers and for metabolic enzymes. The metabolic profile of lung tumours harvested from CRISPR/Cas9 mice that lack expression of Lkb1, p53 and express enhanced KRas, was significantly different from the metabolic profile of lungs harvested from control mice, favouring a switch from glycolysis to mitochondrial metabolism. Acetylation and methylation modifications to histones 3 (H3) and H4 were significantly different compared to control mice, as was the macrophage activation profiles.
    
    Conclusion:
    The goal of our study was to identify and characterize the molecular profile of early stage lung cancers. We conclude from our study that patients with lung cancers that lack expression of LKB1 are likely to respond favourably to interventions that simultaneously target aberrant metabolism with modifiers of tumour epigenetic landscape. Our findings suggest that loss of LKB1 expression serves as a marker for lung cancers that are metabolically and epigenetically challenged.