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Laura Saunders



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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-02 - Dynamics of DLL3 and ASCL1 Expression in SCLC Over Disease Course (ID 12609)

      12:00 - 13:30  |  Author(s): Laura Saunders

      • Abstract
      • Slides

      Background

      SCLC is a high-grade neuroendocrine malignancy highly responsive to first-line therapy, etoposide plus platinum (EP), but increasingly resistant to subsequent lines of therapy. Because SCLC is rarely biopsied following the initial diagnosis, the dynamics of expression of therapeutically relevant biomarkers in relapsed disease are poorly understood. ASCL1 is an oncogenic driver of SCLC and directs transcription of delta-like protein 3 (DLL3), an atypical Notch receptor family ligand involved in neuroendocrine tumorigenesis and the target of the antibody drug conjugate rovalpituzumab tesirine (Rova-T™). We investigated ASCL1 and DLL3 expression in SCLC patient (pt) tumor biopsies and patient-derived xenografts (PDXs) collected serially from time of diagnosis (pre-treatment) and after progression following ≥1 lines of therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Fresh cut, formalin fixed, paraffin embedded tissue from primary SCLC tumors and PDXs was sectioned and stained with mouse monoclonal antibodies against DLL3 (SC16.65) and ASCL1 (SC72.201) on the Dako platform. ASCL1 and DLL3 expression were scored as a percent of positive cells and correlated with each pt’s treatment history.

      4c3880bb027f159e801041b1021e88e8 Result

      Among biopsies and/or PDXs derived over serial time points, 6 cases had baseline positive DLL3 expression ranging from 15-80% of cells with a mean of 50% pre-EP. All 6 remained positive following progression after EP, with DLL3 expression ranging from 10-100% of cells with a mean of 66%. Up to 7 serial tissue or PDX samples were available over the course of multiple treatments for 2 pts, and DLL3 and ASCL1 expression remained consistent over time, being strongly positive in 1 case and negative in the other. Among biopsies and PDXs established at matched time points, ASCL1 and DLL3 expression were consistent in 7/7 and 7/8 cases, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ASCL1 and DLL3 expression remain mostly consistent pre- and post- chemotherapy in pts with SCLC, suggesting that expression of these biomarkers in archival tissue likely accurately estimates expression even after intervening treatments. Furthermore, PDXs derived both from biopsies and circulating tumor cells maintain ASCL1 and DLL3 expression that reflects the pt tumor, supporting use of PDXs to model pt tumor biology.

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