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Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

ABSTRACT: The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3? inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/carboplatin in 20-25% of the SCLC lines. Only 10-15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

SUBMITTER: Teicher BA

PROVIDER: S-EPMC5548882 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Teicher Beverly A BA Silvers Thomas T Selby Michael M Delosh Rene R Laudeman Julie J Ogle Chad C Reinhart Russell R Parchment Ralph R Krushkal Julia J Sonkin Dmitriy D Rubinstein Larry L Morris Joel J Evans David D

Cancer medicine 20170801 8

The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in ...[more]

PMID: 28766886

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Project description:BackgroundThere are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC.MethodsWe reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan-Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively.ResultsThe response rate was 72.6% (95% confidence interval: 63.0-82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9-5.9) months and 15.4 (95% CI: 11.4-16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0-1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p<0.0001).ConclusionsThis is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients.

Project description:BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is an aggressive disease with poor survival, and platinum-etoposide chemotherapy is indicated as the mainstay of treatment. In this study, we compared the efficacy and safety between the cisplatin plus etoposide (EP) and carboplatin plus etoposide (EC) regimens.MethodsA total of 1305 patients with previously untreated ES-SCLC were included in this study. Data from five trials were collected from the public database Project Data Sphere. Survival analysis and adverse events (AEs) analysis were conducted.ResultsOf the 1305 patients, 800 received the EC regimen whereas 505 received the EP regimen as their front-line treatment. Overall, the median progression-free survival (PFS) and the median overall survival (OS) were 172 and 289 days, respectively. The EP and EC treatment groups did not have significantly different PFS or OS. After adjusting for age, sex, body mass index (BMI) and Eastern Cooperative Oncology Group (ECOG) performance status (PS), the EP regimen was independently associated with better PFS (hazard ratio [HR] = 0.76, 95% CI = 0.63-0.92, p = 0.0041) and OS (HR = 0.79, 95% CI = 0.64-0.97, p = 0.0220) among patients who were overweight and obese (BMI ≥ 25 kg/m2). In the safety analysis, patients who received the EC treatment experienced significantly more grade ≥ 3 AEs (n = 599, 74.9%) than those who received the EP treatment (n = 337, 66.7%; p = 0.002). Furthermore, the EC regimen was associated with a higher risk of grade 3-4 neutropaenia (p = 0.001), thrombocytopaenia (p < 0.001) and hyponatraemia (p = 0.036), whereas the EP regimen was associated with a higher risk of grade 3-4 vomiting (p = 0.021).ConclusionsIn summary, this study presented the efficacy and safety of the EC and EP regimens in patients with ES-SCLC in the first-line setting. Patients who are overweight and obese benefit more from the EP regimen than EC regimen. Approaches to define the optimal chemotherapy regimen in different BMI subgroups are needed.

Dataset Information

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

Publications

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent.

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