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M. Meerang
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.06 - Refinement of the Prognostic miR-Score for Use in Diagnostic Specimens from Chemo-Naïve Malignant Pleural Mesothelioma Patients (ID 5045)
15:05 - 15:15 | Author(s): M. Meerang
- Abstract
- Presentation
Background:
A 6-microRNA signature (miR-Score, Kirschner et al 2015) was previously demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy). In the present study we investigated these microRNAs in an independent cohort of MPM patients all treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP). The main focus of the study was to evaluate the possible effects of induction chemotherapy on microRNA expression and to refine and validate the miR-Score for use in chemo-naïve diagnostic specimens.
Methods:
We identified a cohort of 120 MPM patients who received chemotherapy followed by EPP between 1999 and 2014 at University Hospital Zurich. At present microRNA analysis (RT-qPCR) has been carried out in 34 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Paired-samples t-test was employed to determine differences in microRNA expression pre- and post-chemotherapy. Accuracy of the miR-Score in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis. In addition, binary logistic regression modelling was used to build a refined miR-Score.
Results:
Applying the miR-Score to chemo-naïve diagnostic specimens revealed an area under the ROC curve (AUC) of 0.65 (95% CI: 0.46-0.84), and the same analysis on the EPP specimens gave an AUC of 0.57 (95% CI: 0.37-0.77). Therefore, the accuracy of the miR-Score was lower than observed in the previous study. However, pairwise comparison of microRNA expression before and after chemotherapy showed that although not reaching statistical significance, the levels of several microRNAs were lower following induction chemotherapy. We next employed binary logistic regression modelling on microRNA levels in chemo-naïve tissue to determine whether a refined microRNA signature less susceptible to chemotherapy-induced changes could be created. A refined miR-Score consisting of miR-221 and miR-30e, the two microRNAs least affected by chemotherapy, achieved AUCs of 0.77 (95% CI: 0.61-0.94) and 0.80 (95% CI: 0.64-0.96) in diagnostic and EPP specimens, respectively. When applied to samples from the previous study, the refined score resulted in an AUC of 0.72 (95% CI: 0.54-0.90).
Conclusion:
This validation and refinement study has shown that the expression of several miR-Score microRNAs appears to be affected by standard chemotherapy. A refined miR-Score was generated which is less susceptible to the effect of chemotherapy and may have prognostic value when applied to diagnostic specimens. Further validation in additional paired samples and investigation of the effect of cisplatin, pemetrexed and gemcitabine on microRNA expression are ongoing.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-001 - Targeting Cullin Ubiquitin Ligase Leads to Growths Arrest in Malignant Pleural Mesothelioma Cells (ID 5486)
14:30 - 14:30 | Author(s): M. Meerang
- Abstract
Background:
Mutation of the tumor suppressor gene NF2 was detected in 30-40% of malignant pleural mesothelioma (MPM) patients. NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase. Cullin4A (CUL4A) gene amplification and its’ overexpression has been detected in MPM cell lines and tumors. We hypothesized that cullin4 is a potential treatment target for MPM. Cullins’ activity can be blocked by the inhibition of neddylation, a post-translational modification for cullins. In this study we assessed the efficacy of pevonedistat, an inhibitor of protein neddylation.
Methods:
Thirteen MPM cell lines and 3 MPM primary cells grown in monolayer (2D) were employed to assess the efficacy of pevonedistat in vitro compared to normal mesothelial cells, using MTT assay. The expression of cullins was assessed by quantitative real time PCR and western blot. Cell cycle was analyzed by flow cytometry. Four cell lines were cultured in multicellular spheroid (3D) format and measured for viability by acid phosphatase assay.
Results:
Five MPM cell lines overexpressing CUL4A are highly sensitive to pevonedistat (figure1). The treatment induced G2 cell cycle arrest and accumulation of cells containing >4N DNA content, representing cells undergoing DNA re-replication. DNA re-replication is known to be mediated by the accumulation of a DNA replication licensing factor, CDT1. Indeed, higher CDT1 accumulation was detected in the sensitive compared to the resistant cell lines. All primary cells showed no CUL4A overexpression compared to normal mesothelial cells, nonetheless 2 of them were sensitive to pevonedistat. Interestingly, these cells exhibited higher levels of neddylated (activated) CUL4A and higher CTD1 accumulation following the treatment. Cells lines overexpressing CUL4A remained sensitive to pevonedistat when grown in 3D spheroids. Figure 1
Conclusion:
Inhibition of cullins by pevonedistat induced growth arrest preferentially in MPM cells overexpressing CUL4A in 2D and 3D cultures. The major mechanism seems to be mediated by DNA re-replication induced by CDT1 accumulation.
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P3.03-044 - Is Toxicity Increased by Adding Intraoperative Chemotherapy to Preoperative Induction Chemotherapy for Mesothelioma Patients? (ID 5945)
14:30 - 14:30 | Author(s): M. Meerang
- Abstract
Background:
Intracavitary application of chemotherapy after mesothelioma resection is intended to prevent local recurrence. In the present study, we compared hematological and renal toxicity of patients treated with or without additional intracavitary cisplatin-fibrin after (extended) pleurectomy/decortication ((e)P/D) and previous i.v. induction chemotherapy with cisplatin/pemetrexed (CTX).
Methods:
Hemoglobin values, platelet count as well as urea, creatinine, sodium, potassium and magnesium values of 32 patients treated with (e)P/D were compared to the first five patients receiving 44mg/m[2] BSA intracavitary cisplatin-fibrin in our INFLuenCe-Meso phase II trial (www.clinicaltrial.gov NCT01644994). The median time between last cycle of CTX and surgery was 6 weeks (1-14 weeks). The blood values were measured on postoperative day (POD) 1 to 5, 7, 10 and 14 if available. For statistical comparison Mann-Whitney U test was used.
Results:
No significant difference between the 2 groups was observed in the preoperative baseline blood samples. On POD3 hemoglobin dropped significantly more in patients with cisplatin-fibrin application (Figure 1A). However, the use of blood transfusion was not significantly different in both groups. Also sodium, potassium (Figure 1B) and magnesium levels were significantly lower in the study patient group. Disorders in electrolytes were however never reflected in clinical symptoms and reached only in 3 patients a CTCAE level ≥3. There was no significant difference in platelet count, urea and creatinine levels. Figure 1
Conclusion:
The present analysis shows that additional intracavitary cisplatin-fibrin after eP/D and previous i.v. induction chemotherapy with cisplatin/pemetrexed can lead to electrolyte disorders and drop in hemoglobin concentration. However, none of the mentioned laboratory findings had a clinically significant impact on the patients’ postoperative course.
