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Michael Lanuti
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-32 - Knockdown of CENPF Gene Inhibits the Progression of Lung Adenocarcinoma Mediated by ERβ2/5 Pathway (Now Available) (ID 1882)
09:45 - 18:00 | Author(s): Michael Lanuti
- Abstract
Background
The signal transduction pathway of estrogen receptors (ER) mainly includes gene and non-gene pathways. Studies have shown the gene pathway of ER is related to expression of nuclear proteins, and our previous research showed that estrogen promotes progression of lung cancer via ERβ. Four GEO datasets (two NSCLC, two lung adenocarcinomas (LUAD)) were analyzed and found elevated expression of the nuclear protein gene, human centromere protein F (CENPF) in LUAD. This study explores the relationship between ERβ and CENPF in lung cancer.
Method
We verified the above phenomenon by analysis of Oncomine database, specimen transcriptome and protein mass spectrometry in LUAD patients. Co-expression of CENPF and ERβ in the nucleus of LUAD cells were confirmed by cellular immunofluorescence and tissue microarray analysis. This result was also verified by analysis of GEPIA and TCGA databases. Finally, cell culture and animal models of lung cancer were treated with a CENPF knockdown gene and/or combination with fulvestrant (ERβ inhibitor) and assessed for cell survival and tumor volume. Mechanism was assessed with markers of ER β2/5 or surrogates of other signaling pathways.
Result
The high expression of CENPF was associated with high TNM stage (p <0.001, Figure 1A), low overall survival (OS, p =0.01, Figure 1B) and low disease-free survival (PFS, p =0.027) in LUAD. CENPF and ERβ2/5 were highly co-expressed and this co-expression positively related with high TNM stage in LUAD patients (p <0.001). Knockdown of CENPF gene significantly inhibited the biological effects of LUAD cells (p <0.05, Figure 1 C-D), tumor growth in mice (p <0.05, Figure 1 E, F, H), and the expression of ERβ2/5 (p <0.05, Figure 1 G).
Conclusion
Both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown of the CENPF gene can inhibit the progression of LUAD by inhibiting the expression of ERβ 2/5.
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P1.03-42 - Angiotensin System Inhibitors Improve Survival in Stage IIIA NSCLC and Show Anti-Tumor Effect in Combination with Chemotherapy in a Model of NSCLC (Now Available) (ID 1415)
09:45 - 18:00 | Author(s): Michael Lanuti
- Abstract
Background
There is increasing interest in the renin-angiotensin system and its influence on tumor microenvironment. This study investigates the anti-tumor effect of angiotensin system inhibitors (ASI) on the multi-modality treatment of stage IIIA NSCLC and examines a potential mechanism in a murine model of lung cancer.
Method
We retrospectively reviewed the medical records of 125 patients at a single institution diagnosed with clinical stage IIIA NSCLC who underwent induction chemo-radiotherapy followed by surgery between 2009-2015. Overall survival was compared in patients on or off ASI's. To assess the antitumor efficacy and mechanism of ASI’s, cell culture models of lung cancer were treated with losartan or combination losartan+cisplatin and assessed cell survival. Mechanism was investigated with markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, PD-L1). Losartan was then tested in a murine model of lung cancer.
Result
ASI was associated with improved overall survival on multi-variate analysis of patients treated with multi-modality therapy for stage IIIA NSLC (p =0.047) [Figure 1A]. Losartan(≥0.5μM) significantly inhibited proliferation and migration of multiple human lung cancer cells, (H441, H358, H1299, SW1573) and a murine lung cancer adenocarcinoma, TC-1. The combination of Losartan and cisplatin significantly improved the cytotoxic effect of cisplatin in lung cancer cells in vitro (SW1573 p =0.020, TC-1 p =0.012) and reduced the tumor volume of (SW1573-Nude mice, p =0.045 [Figure 1B]; TC-1-C57BL/6 mice, G, p =0.001) in a murine flank tumor model as compared to single drug treatment. Combination treatment also significantly inhibited epithelial to mesenchymal transition and down-regulated the expression of AKT, Stat3, and PD-L1.
Conclusion
ASI treatment influences survival in stage IIIA NSCLC. Losartan improves the anti-tumor effect of cytotoxic chemotherapy in lung cancer invitro and significantly reduces tumor burden in a murine lung cancer model. This study suggests a role for ASI therapy in the treatment of lung cancer.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-101 - Multiple Chemotherapy-Based Combination Therapy Strategies for Advanced Lung Cancer Patients: A Systematic Review and Network Meta-Analysis (Now Available) (ID 1872)
10:15 - 18:15 | Author(s): Michael Lanuti
- Abstract
Background
The treatments for patients with advanced lung cancer focus on chemotherapy, targeted therapy and immunotherapy, or a combination of multiple treatments. This study compares various chemotherapy-based combination therapies to identify the best one for patients with advanced lung cancer.
Method
A literature search was performed (PubMed, EMBASE and Medline) for randomized controlled trials of advanced lung cancer combination therapy from 2008 to 2018. Primary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), adverse as second outcome indicators. A Bayesian mesh meta-analysis for multiple treatment strategies was implemented. The results of four outcome variables were combined to find the best chemotherapy-based combination therapy strategy.
Result
The analysis included 43 studies and five combination therapies: Chemotherapy/chemotherapy plus placebo (CT), CT plus one targeted therapy drug (CT+T), CT plus 2 targeted therapy drugs (CT+T+T), chemotherapy combined with immunotherapy (CT+IO) or chemotherapy combined with biotherapy (CT+B) (Figure 1 A-B). Hazard ratios for OS of CT+T, CT+T+T, CT+IO, CT+B compared to CT were 0.92 (CI 0.86, 0.97, p =0.0154), 0.90 (CI 0.74-1.1), 0.82 (CI 0.71-0.93, p =0.0069) and 1.1 (CI 0.77-1.5). And the HRs of CT+T+T, CT+IO compared to CT+T were 0.98 (CI 0.82-1.2), 0.89 (CI 0.77, 1.0). Finally, comparing with CT+T+T, CT+IO had longer survival 0.91 (CI 0.71-1.1). With the same tendency as PFS/ORR and OS (Figure 1 C-H), CT+IO showed the best therapeutic benefits, and its treatment-related adverse reaction rate was the lowest. Among immunotherapy drugs in these studies, pembrolizumab showed superior efficacy.
Conclusion
Among multiple chemotherapy-based combination therapy strategies, chemotherapy combined with immunotherapy is the best choice for patients with advanced lung cancer. Moreover, the results also showed that the PD-1 inhibitor (pembrolizumab) is superior to the CTLA4 inhibitor (ipilimumab).
