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Pinaki Bose



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    MA04 - Models and Biomarkers (ID 122)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA04.10 - Development and Validation of a Gene Expression-Based Prognostic Signature in Early-Stage Squamous Cell Carcinoma of the Lung (Now Available) (ID 2643)

      13:30 - 15:00  |  Presenting Author(s): Pinaki Bose

      • Abstract
      • Presentation
      • Slides

      Background

      Squamous cell carcinoma of the lung (SqCCL) accounts for about 30% of all lung cancers and is usually associated with smoking. The clinical outcomes of early stage SqCCL are heterogeneous; while 60% of Stage I and II SqCCL patients never present with recurrence after surgery, the remaining will ultimately succumb to the disease. Therefore, a robust prognostication tool is an unmet clinical need. Here, we describe the development and validation of a gene expression-based prognostic signature in Stage I and II SqCCL patients.

      Method

      A total of 673 primary tumour samples obtained from surgically resected Stage I and II SqCCL patients were included in this study. The Cancer Genome Atlas (TCGA) cohort contained 365 patients with gene expression data generated using RNA sequencing (RNAseq). Five data sets (GSE30219, GSE37745, GSE50081, GSE4573, GSE14814) containing 308 patients profiled using Affymetrix microarrays were obtained from the Gene Expression Omnibus (GEO) database; batch effect mitigation of gene expression data was performed using ComBat. An additional cohort of consecutive Stage I and Stage II SqCLC patients was assembled at the Tom Baker Cancer Centre (TBCC), University of Calgary and gene expression was profiled using RNAseq. We performed a two-stage development of the gene signature by performing penalized elastic net Cox regression analysis in the TCGA training cohort followed by refinement of the gene list in the compiled GEO database patients. Final validation was performed using the in-house TBCC cohort. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary outcomes of interest, respectively.

      Result

      All datasets used in this study were found to consist of patients with comparable clinical characteristics. A gene expression signature associated with PFS was developed in TCGA cohort that significantly stratified patients into high and low risk groups. The signature was refined in the complied GEO database cohort and validated in the U of C cohort. The signature also effectively stratified patients into high and low risk groups based on OS. We are currently performing multivariable analysis of the refined gene signature, adjusting for covariates of known prognostic value.

      Conclusion

      Our signature, if prospectively validated, will guide clinical decision making in SqCCL. Effective risk stratification using our signature may identify Stage I patients that will benefit from adjuvant therapy and stage II patients that could be spared adjuvant treatment following surgical resection.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-41 - The Combination of the PARP Inhibitor Olaparib and the ATR Inhibitor VE-821 Selectively Targets ATM-Deficient Lung Cancer Cells (ID 620)

      09:45 - 18:00  |  Author(s): Pinaki Bose

      • Abstract
      • Slides

      Background

      The driving principle behind precision medicine is to specifically target genetic variations that arise in tumorigenesis while leaving normal cells unaffected. Mutations in Ataxia Telangiectasia Mutated (ATM) may offer such a therapeutic target. ATM is mutated in approximately 12% of lung cancers and up to 40% of lung adenocarcinoma have been reported to lack ATM protein expression. ATM is an apex signaling kinase that responds to DNA-double strand breaks, playing a direct role in DNA repair as well as the initiation of signaling cascades that can lead to cell cycle arrest and apoptosis. We asked whether ATM-deficient human lung cancer cells are sensitive to the poly-ADP ribose polymerase (PARP) inhibitor olaparib, and investigated the mechanism of action of olaparib in these cells.

      Method

      We analyzed drug sensitivity for 61 lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project and deleted ATM from lung adenocarcinoma A549 cells using CRISPR/Cas9. We determined the effects on cell viability using trypan blue exclusion and clonogenic survival assays. To investigate the mechanism of sensitivity of ATM-deficient cells to PARP and ATR inhibitors we used flow cytometry and cell viability assays as above.

      Result

      We observed a positive correlation between olaparib IC50 values and ATM mRNA expression. ATM mutant cell lines were more sensitive to olaparib compared to ATM wild-type cell lines or cell lines with amplified ATM. Additionally, ATM-deficient lung cancer cells were sensitive to olaparib, as are lung cancer cells (A549) with CRISPR/Cas9 deletion of ATM. Mechanistically, olaparib caused the temporary and reversible accumulation of G2 phase cells in ATM-deficient cells which manifested as a decrease in proliferation in both the trypan blue exclusion assay and clonogenic survival assay. Olaparib did not induce cell death in ATM-deficient cells, however cell death was induced when olaparib was used in combination with the ATR inhibitor VE-821.

      Conclusion

      We show that olaparib acts as a cytostatic agent in ATM-deficient lung cancer cells, inducing a reversible and temporary growth arrest in G2 phase. Only when combined with the ATR inhibitor VE-821 was cell death observed and only in ATM-deficient cells. Our data suggest that patients with ATM-deficient lung cancer could benefit from combinatorial treatment with PARP and ATR inhibitors.

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