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James H Laird



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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.01 - PARP Inhibitor Radiosensitization of Small Cell Lung Cancer Differs by PARP Trapping Potency (ID 13358)

      15:15 - 15:20  |  Author(s): James H Laird

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in six SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. The dose modification factor (DMF), defined as the ratio of RT dose needed to achieve an equivalent level of survival with RT alone compared to that for RT plus drug, was calculated at 37% survival. Phosphorylated gH2AX sub-nuclear foci were assessed by immunofluorescence to quantify double-stranded DNA breaks (DSBs). Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.

      4c3880bb027f159e801041b1021e88e8 Result

      Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays with a talazoparib dose of 20 nM demonstrating a DMF ranging from 1.61 – 2.88 in 4 cell lines with 0.2 nM demonstrating a DMF of 1.56 in 1 additional cell line. We confirmed radiosensitization in 3 of 3 cell lines by CSAs with DMF ranging from 1.40 – 2.20. To determine effects of PARP trapping on radiosensitization, we identified that concentrations of 200 nM talazoparib and 1600 nM veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization (DMF 3.3 with talazoparib vs DMF 1.0 with veliparib). This observation further correlated with an increased number of DSBs induced by talazoparib as compared to veliparib, where we found that talazoparib produced more residual DSBs than veliparib and DMSO with IR (gH2AX foci mean per cell: talazoparib 53.5, veliparib 33.5, DMSO 25.5) and without IR (40.0, 19.6, 14.6). Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PARP inhibition effectively sensitizes SCLC cell lines and PDXs to RT, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of RT in SCLC.

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