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Laila C. Roisman



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.05 - The Micro-Environmental Cross Talk Between Mast Cells and Lung Cancer Cells Through Cell-to-Cell Contact (ID 11140)

      14:00 - 14:05  |  Author(s): Laila C. Roisman

      • Abstract
      • Presentation
      • Slides

      Background

      Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement and implying metabolic changes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact mediated activation. Lysates of MCs were tested for protein expression and posttranslational modifications (i.e. phosphorylation) by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least twice.

      4c3880bb027f159e801041b1021e88e8 Result

      H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells. In addition, we discovered that the AKT activation was inhibited by A3 receptor and PI3K inhibitors but not by CD 73 inhibitors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. Furthermore, we can conclude that H1299 membranes activate AKT in an A3 receptor dependent mechanism that is mediated by PI3K.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-02 - Osimertinib for EGFR-Positive Advanced NSCLC with Brain Metastases: Preliminary Analysis of an Open-Label, Two-Arm, Phase 2 Study (ID 13020)

      16:45 - 18:00  |  Author(s): Laila C. Roisman

      • Abstract
      • Slides

      Background

      Osimertinib is an EGFR tyrosine-kinase inhibitor (TKI) selective for both EGFR TKI sensitizing and Thr790Met resistance mutations. While intracranial activity of osimertinib was observed in EGFR-mutant NSCLC in larger trials, a study focusing on patients with brain metastases was not reported yet.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase 2, open-label, two-arm study enrolled patients with EGFR-mutant, advanced NSCLC and at least one asymptomatic brain metastasis. Treatment-naïve (arm A) and Thr790Met-positive patients who progressed on EGFR-TKI therapy (arm B) received osimertinib 80 mg QD. Dose escalation (160 mg QD) was performed in cases of intracranial progression without symptomatic systemic progression. The primary endpoint was intracranial metastasis response. The trial is ongoing (NCT02736513 at ClinicalTrials.gov) and here we present a preliminary analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Between May 31, 2016, and November 30, 2017 (data cutoff), 20 patients started osimertinib (arm A=15, arm B=5). Median duration of follow-up was 43 weeks. Intracranial response was achieved in 11 (73%; 95% CI 45%-92%) of 15 arm A and in four (80%; 95% CI 28%-99%) of five arm B patients. Dose escalation was performed in four cases (arm A=2, arm B=2), with one continuous response (25%, 95% CI 5%-70%). Ten of 15 patients (67%) in arm A and one of five patients (20%) in arm B continue responding to osimertinib 80 mg at data cutoff. Median intracranial PFS (80 mg) was not available for arm A (95% CI 232 days–NA), and was 510 days in arm B (95% CI 161–not available). Toxic effects were similar to previous reported data.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib shows equal intracranial and systemic activity with minor side-effects in EGFR-mutant NSCLC as first-line, as well as in previously treated Thr790Met-positive patients. It might therefore be a reasonable treatment for these patient populations and defer brain radiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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