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John Poirier
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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): John Poirier
- Abstract
- Presentation
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.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS32 - SCLC - From Benchside to Bedside - Clinical Science Session (ID 810)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 107
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MS32.06 - Epigenetic Targets (ID 11545)
14:45 - 15:00 | Presenting Author(s): John Poirier
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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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P3.12-06 - SLFN11 Expression and Efficacy of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 14113)
12:00 - 13:30 | Author(s): John Poirier
- Abstract
Background
Veliparib (V),an oral small molecule inhibitor of poly (ADP) ribose polymerase (PARP) enhanced cytotoxic chemotherapy in preclinical models of small cell lung cancer (SCLC). The combination of V with cisplatin/etoposide (CE) doublet showed efficacy improvement as first-line therapy of extensive stage SCLC (ES-SCLC) with adjusted PFS HR: 0.63 1-sided p=0.01. There was differential treatment effect by strata (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets) highlighting the need to identify patient subset most likely to benefit. SLFN11 expression was previously shown to be associated with benefit of V when combined with temozolomide in relapsed SCLC and also predicted benefit of CE in preclinical models. We assessed the utility of SLFN11 as a predictive biomarker in the context of E2511 frontline clinical trial.
a9ded1e5ce5d75814730bb4caaf49419 Method
Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis looking at SLFN11 expression by immunohistochemistry. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing SLFN11 (+) and (-) patients using a one-sided 0.025 level logrank test.
4c3880bb027f159e801041b1021e88e8 Result
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Clinical outcome differences based on SLFN11 expression is ongoing and will be presented at the meeting.
8eea62084ca7e541d918e823422bd82e Conclusion
Pending ongoing analysis of correaltion of biomarker with clinical outcomes
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