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M.A. Hoda
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MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
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MINI24.09 - Cell-Free MicroRNA miR-625-3p Is Elevated in the Blood of Patients with Thoracic Malignancies (ID 1282)
17:30 - 17:35 | Author(s): M.A. Hoda
- Abstract
Background:
In most instances definitive diagnosis of malignant pleural mesothelioma (MPM) requires a tissue biopsy of sufficient size. As a biopsy is not always feasible, the identification of an accurate biomarker easily measured in blood would represent an important step forward. A recent study indicated that microRNA miR-625-3p was present in elevated concentration in plasma or serum of MPM patients compared to healthy controls and asbestosis patients. (Kirschner et al, JTO; 7:1184). In this study, we have further investigated the diagnostic potential of miR-625-3p.
Methods:
MiR-625-3p and other microRNAs were measured by RT-qPCR in two independent series of MPM patients and controls. After exclusion of haemolysed samples and those yielding RNA of insufficient quality, series 1 consisted of serum samples from 73 MPM patients, 69 healthy volunteers and 64 patients with non-small cell lung cancer (NSCLC) collected at the Netherlands Cancer Institute (NKI) between 1994 and 2013. The second series consisted of plasma samples from 29 MPM patients and 35 healthy volunteers collected in Vienna and Hungary (V/H) between 2011 and 2013. Additionally levels of soluble mesothelin-related protein (SMRP) were assessed (ELISA) in the NKI series.
Results:
Analyses of samples from patients and controls in the NKI series revealed that serum miR-625-3p concentrations were on average 5.35-fold higher (p=0.0054) in MPM, and 3.47-fold (p=0.003) in NSCLC than in control samples. Levels in MPM patients were 1.54-fold higher than in NSCLC patients but this did not reach statistical significance (p=0.273). Compared to healthy controls, the areas under the ROC curve (AUC) were 0.82 (95% CI: 0.75-0.89) for MPM and 0.75 (95% CI: 0.67-0.84) for NSCLC. In the samples of the V/H series, plasma miR-625-3p concentrations were on average 1.98-fold (p<0.001) higher in MPM patients than in healthy volunteers, with an AUC of 0.80 (95% CI: 0.69-0.91). Assessment of SMRP in the NKI series revealed AUCs of 0.69 (95% CI: 0.59-0.78) differentiating MPM from healthy individuals and 0.65 (95% CI: 0.54-0.75) separating MPM from NSCLC, comparable to AUC values reported earlier.
Conclusion:
Data from two independent validation series confirms the previously observed increased abundance of miR-625-3p in blood from MPM patients. However, the miR-625-3p levels observed in NSCLC patients show that elevation of the level of this microRNA in plasma/serum is not restricted to MPM. Further studies into combinations of microRNAs and SMRP (diagnostic signature) in MPM are warranted.
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ORAL 14 - Biology 2 (ID 112)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:T. Nakano, P. Baas
- Coordinates: 9/07/2015, 16:45 - 18:15, 702+704+706
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ORAL14.07 - Preclinical Investigation of the Therapeutic Potential of Nintedanib in Malignant Pleural Mesothelioma (ID 2655)
17:50 - 18:01 | Author(s): M.A. Hoda
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.
Methods:
21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.
Results:
Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).
Conclusion:
Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-103 - Evaluation of the TGF Beta Superfamily Member Activin-A as a Novel Circulating Prognostic Marker in Lung Cancer (ID 2720)
09:30 - 09:30 | Author(s): M.A. Hoda
- Abstract
Background:
Identification of biomarkers that can facilitate early detection and therapeutic decision making in lung cancer (LC) is urgently needed. Growth factors of the activin family are deregulated in a number of malignancies including thoracic tumors. Recent studies provided data regarding the tumor tissue expression levels of activin-A in lung adenocarcinoma (ADC): High activin-A expression was associated with poor prognosis, enhanced metastasis and shorter progression-free survival in stage I ADC. Since activin-A is secreted to the circulation and can be detected in plasma, this study aims to determine, for the first time, the value of circulating activin-A as a biomarker in LC patients.
Methods:
Plasma samples from patients with small cell lung cancer (SCLC, n= 79), ADC (n=87) and squamous cell carcinoma (n=36) were collected between 2009 and 2013 at the time of diagnosis or before surgical resection. Additional samples, serving as age- and sex-matched controls, consisted of individuals without malignancies (n=66). Measurement of samples was performed using the Quantikine activin-A Elisa kit (R&D Systems) and all statistical analyses were performed using the PASW Statistics 20.0 package and GraphPad Prism 6.0.
Results:
Mean plasma activin-A levels (PAL) (pg/ml) were the following: 628,8±38,42 (ADC, range: 112,4-1875), 613,5±68,22 (SCC, range: 194-2076), 771±77,06 (SCLC, range: 174,1-3627) and 433,3±16,27 (controls, range: 194,1-808,8). A gender-related variation in the PAL of controls (female (n=31, mean PAL 469,5±24,54 (range 212,95-808,79)) vs. male (n=35; mean PAL 401,3±20,49 (range 194,1-759,02)), p= 0.0319) was observed. PAL was significantly increased in patients with ADC (p=0.0009), SCC (p=0.0061) and SCLC (p<0.0001) compared to controls. There was no difference in PAL with regard to patients´ age, gender, BMI, smoking status or other co-morbidities in all 3 LC types. A significant TNM stage-dependent increase of PAL was observed in all 3 LC types. PAL was elevated in T3 SCC, in T4 ADC and in T3 and T4 SCLC. PAL was also clearly associated with N status and metastatic disease in all 3 LC types. Importantly, in case of SCLC, PAL was associated with extensive disease and showed metastatic site specificity. In ADC patients, elevated PAL was associated with significantly worse overall survival (OS) (p<0.0001). Of note, in locally advanced ADC, elevated PAL also proved to be a significant negative prognosticator (p=0.048). Moreover, elevated PAL was associated with a poor OS in SCLC patients (p=0.0009). Multivariate analysis revealed that PAL was an independent prognostic factor in ADC and SCLC patients. Survival and multivariate analysis data of the SCC cohort will be presented at the conference. ROC curve analysis showed an AUC of 0.691 in SCLC and an AUC of 0,657 in ADC for PAL.
Conclusion:
Our findings suggest that PAL is significantly elevated in a disease stage-dependent manner in LC patients. Moreover, elevated PAL is associated with poor prognosis in ADC and SCLC patients.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-007 - Fibulin-3: A Potential Prognostic Biomarker in Malignant Pleural Mesothelioma? (ID 1668)
09:30 - 09:30 | Author(s): M.A. Hoda
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive asbestos-induced cancer arising from the mesothelium lining the thoracic cavities. The definitive diagnosis of MPM in most instances depends on the availability of a biopsy. A number of biomarkers have been proposed to assist in making the MPM diagnosis but none of them has yet reached the accuracy required for routine clinical use. Among the candidates is the secreted extracellular glycoprotein Fibulin-3 (FBLN3) (Pass et al, NEJM 2012; 367(15)). In this study, we have further investigated the potential of FBLN3 to serve as a biomarker for MPM.
Methods:
Cellular and secreted FBLN3 was measured (ELISA) in MPM and normal mesothelial cell lines, plasma of xenograft tumour-bearing mice, plasma from two independent series of MPM and non-MPM patients, and in malignant and non-malignant pleural effusions. The diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and the Kaplan-Meier method, respectively.
Results:
FBLN3 levels were significantly higher in MPM cells than in mesothelial cells, with a strong correlation between secreted and cellular levels. Human FBLN3 was also detectable in the plasma of tumour-bearing mice, suggesting that MPM cells were the origin of circulating FBLN3. Plasma FBLN3 levels found in MPM patients were lower than previously reported (Pass et al, NEJM 2012; 367(15)), but were comparable to those appearing in subsequent validation studies (Creaney et al, Thorax 2014; 69(10), Corradi et al, Anticancer Res 2013; 33(12)). Plasma FBLN3 was significantly elevated in MPM patients from a Sydney cohort, but far less in a Vienna cohort and the diagnostic accuracy of FBLN3 was insufficient in both cohorts [63%, (95%CI: 50.1-76.4) and 56% (95%CI: 41.5-71.0), respectively]. FBLN3 levels found in pleural effusions were comparable to those reported in previous studies, but the difference between cases and controls did not reach significance. In our series low levels of pleural effusion FBLN3 were again associated (p=0.002) with prolonged survival. In multivariate analysis taking histological subtype, age and gender into account FBLN3 remained significant with a hazard ratio of 9.92 (95%CI: 2.14–45.93).
Conclusion:
FBLN3 is overexpressed in MPM cell lines and may point to a potential oncogenic role for this protein. In contrast to the initial report linking FBLN3 to diagnosis in MPM, the levels of FBLN3 measured in plasma and pleural fluid of our series of MPM patients lacked diagnostic accuracy. However, the potential prognostic value of FBLN3 levels measured in pleural fluid was confirmed and in line with previous validation studies. These data underline the importance of validation studies for newly proposed biomarkers.
