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Francisco Rivas
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)
14:30 - 16:00 | Author(s): Francisco Rivas
- Abstract
- Presentation
Background
Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.
Method
MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.
Result
Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).
Conclusion
CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.
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P2.13 - Staging (ID 315)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Staging
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.13-04 - Molecular Nodal Restaging Based on Embryonic Markers Expression Adds No Relevant Clinical Information in Resected Lung Cancer (ID 1149)
10:15 - 18:15 | Author(s): Francisco Rivas
- Abstract
Background
The relapse rate in non-small cell lung cancer (NSCLC) is high, even in localised disease, suggesting that the current approach to pathological staging is insufficiently sensitive to detect occult micrometastases present in resected lymph nodes. Therefore, we aimed to determine the prognostic value of the expression of embryonic molecular markers in histologically-negative lymph nodes of completely-resected NSCLC.
Method
76 NSCLC patients undergoing radical resection were included. Primary tumours and 347 lymph nodes were studied. The molecular markers finally were selected based on testing of 27 normal lung and 129 lung tumour samples as well as 25 lymph nodes obtained from non-neoplastic diseases. CEACAM5, FGFR2b, and PTPN11 expression levels were evaluated through mRNA analysis using real-time RT-qPCR assay. Statistical analyses included the Kruskal-Wallis test, Kaplan Meier curves, and log-rank tests.
Result
CEACAM5 expression levels were scored as high in 90 lymph nodes (26%). The molecular-positive lymph nodes lead to the restaging of 37 (62%) pN0 patients as molecular N1 or N2 and 5 (31%) pN1 cases were reclassified as molecular-positive N2. Surprisingly, molecular-positive patients (42, 55%) associated with a better OS (overall survival, p=0,04) than molecular-negative patients (34, 45%). FGFR2b overexpression was observed in 41 (12%) lymph nodes leading to the restaging of 17 patients (22%). Again a trend was observed towards a better DFS (disease-free survival) in the restaged patients (p=0,09). PTPN11 expression levels were high in 109 (31%) lymph nodes and led to the restaging of 41 (54%) patients who did not correlate with clinical outcome (p=0,61). The combination of CEACAM5-FGFR2b restaged the same number of patients than CEACAM5 only. Accordingly, high expression levels of CEACAM5 or FGFR2b in the primary tumour were related to better DFS (p<0,06; p<0,02, respectively); PTPN11 did not correlate with prognosis (p=0,37).
Conclusion
Molecular nodal restaging based on expression levels of CEACAM5 and/or FGFR2b, does not add relevant clinical information to pathological staging of NSCLC likely related to the better prognosis of their overexpression in primary tumors.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-10 - Effects of the Omega-6/Omega-3 Ratio on Postoperative Complications After Lung Resection: Preliminary Results (ID 1862)
10:15 - 18:15 | Author(s): Francisco Rivas
- Abstract
Background
In the last 3 decades, the intake of omega-6 (n-6) fatty acids has increased while the intake of omega-3 (n-3) has decreased, leading to an increase in the n-6/n-3 ratio, which is now 20:1. This ratio has been postulated as an inflammatory marker of carcinogenesis, implicated in the development of multiple chronic diseases, and associated with postoperative complications due to the proinflammatory effects of omega 6. Consequently, the preoperative assessment of nutritional markers, together with immunonutrition, represent a promising target to improve outcomes in patients with lung cancer who are candidates for surgical resection. The aim of this study was to assess the effect of the n-6/n-3 ratio on postoperative complications in patients undergoing radical-intent surgery for lung cancer.
Method
Prospective cohort study of 38 patients diagnosed with lung cancer treated with radical surgery between October 2017 and May 2018. The n-6/n-3 ratio was determined immediately prior to surgery with the patient under anesthesia.
Result
Of the 38 surgically-treated patients, 29 were men (76%) and 9 women (24%). Mean patient age was 62 ±10 years. Twelve (32%) patients were active smokers at the time of surgery. The most common histological subtype was adenocarcinoma (60%) and most patients underwent lobectomy (68%). The mean body mass index (BMI) was 27 ±5 and the mean preoperative prognostic nutritional index (PNI) score was 48±7. The mean n-6/n-3 ratio was 20 ±6. The most common complications were prolonged air leak (> 5 days) in 11 patients (29%) and respiratory failure in 6 patients (16%). Patients with prolonged air leak had a significantly higher n-6/n-3 ratio than patients without prolonged air leak (25 ±3 vs. 18 ±6, respectively; p=0.02). Patients with an n-6/n-3 ratio > 20 were significantly more likely (p=0.002) to present prolonged air leak. Neither BMI nor PNI were significant predictors of air leak duration.
Conclusion
These preliminary findings indicate that patients with a higher n-6/n-3 ratio—that is, those with a greater proinflammatory status—were more likely to present prolonged air leak than those with a lower inflammatory status. Based on these encouraging results, we propose to continue with this line of research to better understand the effects and prognostic value of immunonutritional status on the clinical course of patients after lung cancer surgery.
