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Shenglin Ma
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EP1.03 - Biology (ID 193)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.03-16 - Lysimachia Capillipes Capilliposide C Restores Radiation Sensitivity in Radiation Resistant Lung Cancer Cells by Enhancing ERRFI1 Expression (ID 810)
08:00 - 18:00 | Author(s): Shenglin Ma
- Abstract
Background
Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance and local failure remain to be the major clinic problems for lung cancer patients. It is therefore crucial to find new therapeutic targets and/or drugs to enhance the effects of radiation without increasing the adverse effects. Lysimachia capillipes capilliposide C (LC-C) extracts from LC Hemsl. show anti-cancer effects both in vitro and in vivo. The purpose of this study is to investigate a potential therapeutic impact of LC-C as a radiation sensitizer in lung cancer cells.
Method
Non small cell lung cancer (NSCLC) cell line A549 was initially irradiated with a total dose of 60 Gy (3 Gy/Fx, 20 Fx, 2-3 Fx/week) to generate radiation-resistant cancer cell line A549-IR. RNA-seq analysis was used to examine the whole-transcriptome alteration in A549-IR cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of the target gene ErbB receptor feedback inhibitor 1 ( ERRFI1) on radiosensitivity of A549-IR cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blot was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of A549-IR cells in vivo.
Result
ERRFI1 was significantly up-regulated in A549-IR cells when cells were treated with LC-C (IC20=3.5 μM). With irradiation treatment, clonogenic formation decreased in the ERRFI1 overexpressed cells when comparing to the parental cells, with reduced survival fraction-2 value from 0.54±0.07 to 0.24±0.06 (p<0.01). The sensitizing enhancement ratio for LC-C was 1.667. Furthermore, ERRFI1 overexpression may enhance radiosensitivity of A549-IR cells in vitro by inducing G2/M phase arrest and inhibiting DNA damage repair. Overexpression of the ERRF11 decreased the activation of EGFR and STAT3 signaling pathways in A549-IR cells. Knocking down ERRFI1 expression in A549-IR cells attenuated the radiosensitization effect of LC-C. Moreover, in a A549-IR cells-derived xenograft model, combination treatment with LC-C (25 mg·kg−1·d−1, qod, ig) and irradiation (6Gy) dramatically enhanced tumor growth suppression comparing with LC-C or radiation alone.
Conclusion
LC-C can restore the cells' sensitivity to irradiation through regulation of ERRFI1 expression in lung cancer cells. Combination treatment of LC-C and irradiation may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a poteintal therapeutic target to improve radiosensitivity in NSCLCs.
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EP1.03-27 - The Anti-Migration and Anti-Invation Mechanisms of Capilliposide C from Lysimachia Capillipes on Lung Cancer (Now Available) (ID 1678)
08:00 - 18:00 | Author(s): Shenglin Ma
- Abstract
Background
Approximately 50% of lung cancer patients had distant metastases when initial diagnosed. Lysimachia capillipes is one of traditional medicine in China. It is proved to be safety in clinical use. Several studies have showed the antitumor effects of Capilliposide from Lysimachia capillipes (LC) in vitro. Our preliminary data showed LC could inhibit the migration and invasion of lung cancer. This study aims to explore the detailed mechanisms of LC as well as its extracts on lung cancer.
Method
Four non-small cell lines were selected. The invasive response of lung cancer cells was determined by Wound Healing assay. Proteins and the phosphorylation of proteins were evaluated by iTRAQ-based proteomics. The phosphorylation chip was used to evaluate the phosphorylation effect. PC-9 xenografts were used to evaluate the antitumor of LC-C in vivo. Immunohistochemistry (IHC) was used to evaluate the antitumor mechanisms in vivo.
Result
The migration capa city of lung cancer cells was significantly reduced after treatment of LC-C. Proteomics showed there were 364 differentially expressed proteins and 456 differentially expressed phosphorylated proteins in both LC-C treated PC-9 and H1975 cells. Differentially expressed proteins were enriched in EGF receptor signaling pathway, Wnt signaling pathway, Cadherin signaling pathway, Notch signaling pathway, TGF-beta signaling pathway, and p38 MAPK pathway by bioinformatic analysis. Phosphorylation chip showed LC reduced the phosphorylation of AKT, WNK1 and PRAS40, but not EGFR. Western blot showed the phosphorylation of mTOR, AKT and PRAS40 were significantly inhibited after LC-C treatment; besides, the inhibitory effects of AKT and mTOR were dose-dependent. While the total proteins of AKT and mTOR were not changed. Western blot showed the phosphorylation of Smad2 and Smad3 were significantly inhibited after LC-C treatment. Western blot showed E-Cadherin was up-regulated and N-Cadherin was down-regulated after LC-C treatment; while other EMT related proteins including ZO-1, Snail and Vimentin were not changed. Nor did cell adhesion related protein Claudin-1. PC-9 xenograft model showed the tumor growth inhibitory rates were 114.4% in 7 days after LC-C administration. IHC showed the phosphorylation of AKT was down-regulation after LC-C administration, Ki-67 was also down-regulation, while cleaved caspase-3 was not changed.
Conclusion
The study showed LC-C inhibit the growth and the capacity of invasion and migration of lung cancer cells. The detailed mechanisms might crosstalk with several critical pathway such as AKT pathway, TGF-β pathway and EMT.
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MA14 - The Adequate MTarget Is Still the Issue (ID 140)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Diego Signorelli, Juergen Wolf
- Coordinates: 9/09/2019, 15:45 - 17:15, Hilton Head (1978)
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MA14.05 - A Randomized Phase III Trial of Fruquintinib Versus Placebo in Patients with Advanced Non-Small Cell Lung Cancer (FALUCA) (Now Available) (ID 1490)
15:45 - 17:15 | Author(s): Shenglin Ma
- Abstract
- Presentation
Background
Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).
Method
From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.
Result
Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).
Conclusion
The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-19 - Predictive and Prognostic Values of ctDNA Clearance in Osimertinib Treated Advanced Non-Small Cell Lung Cancer Cohort (Now Available) (ID 2061)
09:45 - 18:00 | Author(s): Shenglin Ma
- Abstract
Background
Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. Circulating tumor DNA (ctDNA), validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC patients.
Method
This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC patients who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 patients, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes.
Result
Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 patients, p=0.004) and P53 pathways (43 patients, p=0.032) were associated with shorter OS (p53 was excluded from analysis due to high mutation frequency). Interestingly, patients with undetectable ctDNA at first follow-up (within 50 d, n=41) were correlated with longer PFS (p=0.009) and OS (p=0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 patients experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Patients with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p=0.035) and p53 (p=0.023) mutations at radiological PD. In addition, patients with CNA at radiological PD had shorter PFS (p=0.002) and OS (p=0.052).
Conclusion
This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for patients undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.
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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
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-84 - Serumal SERPINE2 as a Potential Biomarker for Radioresistance in NSCLC (ID 349)
10:15 - 18:15 | Author(s): Shenglin Ma
- Abstract
Background
Radioresistance is the main reason for the failure of clinical radiotherapy in lung cancer. Among the different tumors, SERPINE2 is a protein with anticoagulant properties which could promote or inhibit solid tumor growth. However, its role in the pathogenesis of lung cancer has not been determined.
Method
To get radioresistant cell lines A549R and PC9R, A549 and PC9 cells were treated with fractionated irradiation by high energy X-ray. Cell survival fractions were measured by colony formation assay. Furthermore, we performed RNA-SEQ and protein profiling to screen genes differentially expressed in the A549/A549R and PC9/PC9R cells. To elucidate the biological role of SERPINE2 in radioresistance of NSCLC, we conducted SERPINE2 gene overexpression/knockdown experiments using NSCLC cell lines. The aim of this study was to assess serum SERPINE2 concentrations in a group of 26 NSCLC patients with radiation therapy alone in one course of treatment. Blood samples were collected before treatment. Serum SERPINE2 concentration was measured using specific ELISA methods. We analyzed its prognostic significance regarding outcome analysis, as well as its potential biomarker for radiotherapy.
Result
Two radioresistant lung adenocarcinoma sublines A549R and PC9R were successfully established through dose fractionated irradiation after six months. Results of RNA-SEQ and protein profiling showed the SERPINE2 was higher in A549R and PC9R compared to that in parental cells A549/PC9. We also demonstrated that knockdown of SERPINE2 expression inhibit cell migration and invasion in A549/PC9 cell lines. And the overexpression of SERPINE2 promote cell migration and invasion in H1975/HCC827 cell lines. Knockdown of SERPINE2 expression in the A549R/PC9R by shRNA also reduced significantly cell radiation resistance.The radiobiology parameters, which including SF2, D0, Dq and α/β, were significant differences compared with non-silencing shRNA cells. According to response evaluation criteria in solid tumors, the concentrations of SERPINE2 were significantly higher in PD patients compared with SD and PR.
Conclusion
The preliminary study indicates the SERPINE2 play an important role in the radioresistance of NSCLC and implies the evaluation of SERPINE2 expression in serum may be considered as a potential biomarker in radiotherapy of NSCLC patients. Further research must be explored to clarify the function and mechanism of SERPINE2 in the radioresistance of lung cancer.
