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H. Pass

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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: 8
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      OA22.01 - STELLAR - Interim Results of a Phase 2 Trial of TTFields with Chemotherapy for First Line Treatment of Malignant Mesothelioma (ID 6034)

      14:20 - 15:50  |  Author(s): F. Grosso, J. Mądrzak, R. Ramlau, S. Cedres Perez, L. Crinò, A. Chella, M. Mencoboni, B.I. Hiddinga, G.L. Ceresoli

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, based on low intensity alternating electric fields delivered non-invasively using a portable, home use, medical device. In-vitro, human mesothelioma cells were found to be highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to standard of care chemotherapy.

      Methods:
      The trial will accrue a total of 80 patients with unresectable, previously untreated mesothelioma. Patients are treated with TTFields in combination with pemetrexed and cisplatin or carboplatin. Continuous TTFields at 150 kHz for a minimum of 18 hours/day are applied to the thorax together with standard dosing of chemotherapy. Inclusion criteria include ECOG 0-1, pathological evidence mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients are followed q3 weeks (CT scan q6 weeks) until disease progression. The primary endpoint is overall survival (OS) and secondary endpoints are response rate, progression free survival (PFS) and treatment-emergent toxicity. This prospective, single arm study assumes that historical control has an exponential survival distribution and a median survival of 12.1 Months (Vogelzang et al.). The sample size provides 80% power with a two sided alpha of 0.05 to detect a Hazard Ratio of 0.67 for OS, compared to the historical data.

      Results:
      To date, 42 patients have been enrolled in the trial with an average follow up time of 11.5 months. Median age is 67±9 (range 43-78), 79% are male and 48% smokers. 14% (6 patients) have metastatic disease and 33% (14 patients) have an ECOG score of 1. Median survival has not been reached at this time. The 12-month survival rate is 79.7% (95% CI 57.2-91.2) and median PFS is 7.3 months (95% CI 5.6-NA). No device-related serious adverse events (AEs) have been reported to date. Expected TTFields-related dermatitis was reported in 55% (23 patients). Only 2 patients had grade 3 dermatitis. The following severe (grade 3-4) systemic AEs were reported: hematological (26%), hepatobiliary (2%), respiratory (2%).

      Conclusion:
      These interim results of the ongoing STELLAR study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy for previously untreated mesothelioma patients. The 12-month survival rate was significantly higher, and PFS longer, than that of historical controls reported by Vogelzang et al. Final analysis of the study will be performed after enrollment and follow up of all 80 patients in the study are completed.

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      OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (ID 4191)

      14:20 - 15:50  |  Author(s): F. Grosso, N. Steele, S. Novello, A. Nowak, S. Popat, L. Greillier, T. John, N. Leighl, M. Reck, P. Taylor, N. Pavlakis, J.B. Sørensen, D. Planchard, G.L. Ceresoli, B. Hughes, J. Mazieres, M.A. Socinski, M. Mueller, U. Von Wangenheim, A.B. Loembe, N. Morsli, J. Barrueco, G.V. Scagliotti

      • Abstract
      • Presentation
      • Slides

      Background:
      Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

      Methods:
      Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

      Results:
      87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

      Conclusion:
      Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

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      OA22.03 - HMGB1, a Target for Mesothelioma Therapy and a Biomarker to Detect Asbestos Exposure and to Identify Mesothelioma Patients (ID 5211)

      14:20 - 15:50  |  Author(s): H. Yang, H. Pass, M. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls.

      Methods:
      We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study.

      Results:
      HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival.

      Conclusion:
      Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

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      OA22.04 - Discussant for OA22.01, OA22.02, OA22.03 (ID 6979)

      14:20 - 15:50  |  Author(s): C. Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA22.05 - Breath Analysis by Gas Chromatography-Mass Spectrometry Can Be Used to Screen for Pleural Mesothelioma (ID 4845)

      14:20 - 15:50  |  Author(s): K. Lamote, L. Vandermeersch, H. Van Langenhove, J. Van Cleemput, K. Nackaerts, J.P. Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an asbestos-related tumour with poor prognosis. Since MPM is diagnosed at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome. Breathomics allows to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive biomarkers. Although we were able to discriminate MPM patients from controls using ion mobility spectrometry breathomics, we were not able to identify specific VOCs. Therefore, we aimed to identify VOCs in the breath of MPM persons and persons at risk with gas chromatography-mass spectrometry (GC-MS).

      Methods:
      Fourteen MPM patients, eighteen asymptomatic asbestos-exposed individuals, 16 individuals with benign asbestos-related diseases and fourteen healthy non-exposed persons were included. After 2 hours of fasting, participants breathed tidally for 5 minutes through a mouthpiece connected to a VOC filter. Subsequently, a full vital capacity was captured in a Tedlar bag of which 500 ml was immediately transferred on a Tenax[GR]-column. Samples were thermally desorbed followed by GC-MS analysis (Agilent 6890A–Thermo Focus DSQII). VOCs were manually selected in the chromatogram and standardised to an internal standard (toluene-d8). Only VOCs with a S/N-ratio>10 were used. Using SPSSv23, significant differences were searched and ROC-curves for discriminating MPM from all control groups were constructed. VOCs which had an AUC~ROC~>0.80 are reported.

      Results:
      114 VOCs were selected of which 17 were significantly different between MPM patients and controls. Of these, 7 had AUC~ROC~>0.80 and are possible markers for MPM diagnosis.Figure 1



      Conclusion:
      The large discriminative power and good sensitivity and specificity imply the possibility to use breath analysis for MPM screening. Therefore, persons exposed to asbestos with a positive test should be considered for follow-up in a cost-effective way, decreasing the need for CT-scans and radiation exposure in low-risk persons. Further work includes combining models for discrimination and validating these findings.

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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)

      14:20 - 15:50  |  Author(s): M.B. Kirschner, B. Vrugt, M. Friess, M. Meerang, P. Wild, N. Van Zandwijk, G. Reid, W. Weder, I. Opitz

      • Abstract
      • Presentation
      • Slides

      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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      OA22.07 - Correlation of CT Scan Based Tumor Volume Measurement to Actual Resected Tumor Volume - A New T-Factor? (ID 5958)

      14:20 - 15:50  |  Author(s): O. Lauk, M. Friess, T.D.L. Nguyen-Kim, T. Frauenfelder, S. Hillinger, B. Seifert, I. Inci, W. Weder, I. Opitz

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication.

      Methods:
      From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation.

      Results:
      Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). Figure 1



      Conclusion:
      The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.

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      OA22.08 - Discussant for OA22.05, OA22.06, OA22.07 (ID 7002)

      14:20 - 15:50  |  Author(s): V. Laszlo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    ED13 - Treatment of Malignant Pleural Mesothelioma (ID 282)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 2
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      ED13.01 - Biomarkers in Malignant Pleural Mesothelioma (ID 6495)

      11:00 - 12:30  |  Author(s): H. Pass

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED13.06 - Mesothelioma in a Setting of Germline BAP1 Mutations (ID 6500)

      11:00 - 12:30  |  Author(s): H. Pass

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4[th] decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be ncouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016).

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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
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      OA22.03 - HMGB1, a Target for Mesothelioma Therapy and a Biomarker to Detect Asbestos Exposure and to Identify Mesothelioma Patients (ID 5211)

      14:20 - 15:50  |  Author(s): H. Pass

      • Abstract
      • Presentation
      • Slides

      Background:
      Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls.

      Methods:
      We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study.

      Results:
      HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival.

      Conclusion:
      Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

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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: 1
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      P3.03-021 - When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All? (ID 5025)

      14:30 - 15:45  |  Author(s): H. Pass

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Therefore an urgent need exists to identify new therapies for treating MPM patients. The potential for therapeutically targeting receptor tyrosine kinase (RTK) signalling networks is emerging as a critical mechanism in ‘oncogene addicted’ cancer, with RTK inhibitors evolving as areas of considerable importance in cancer therapy. Furthermore, RTK hetero-dimerization has emerged as a key element in the development of resistance to cancer therapy. As such TKIs which target several RTKs may have superior efficacy compared with TKIs targeting individual RTKs. We and others have identified c-MET, RON, Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate therapeutic targets. A number of orally bioavailable small molecule inhibitors have been developed which can target these receptors. LCRF0004 specifically targets RON, whereas ASLAN002 (BMS-777607) or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, RON, Axl and Tyro3 at nanomolar concentrations. These drugs may therefore have applicability in the treatment/management of MPM.

      Methods:
      A panel of MPM and normal pleural cell lines were screened for expression of Tyro3, c-MET, RON and Axl by RT-PCR, and subsequently examined in a cohort of patient samples comprising benign, epithelial, biphasic, and sarcomatoid histologies by qPCR. The effects of two small molecule inhibitors LCRF0004, ASLAN002 on MPM cellular health were assessed in vitro. The effects of LCRF0004 and ASLAN002 were subsequently examined in an in vivo SQ xenograft tumour model.

      Results:
      Expression of various RON isoforms, c-MET, Tyro3 and Axl were observed in all cell lines. Significantly higher expression of all genes were found in the malignant tumour material versus benign pleura and this was validated in other datasets. Both LCRF0004 and ASLAN002 demonstrated significant anti-tumour efficacy in vitro. In xenograft models ASLAN002 was far superior to LCRF0004.

      Conclusion:
      Our results suggest that a multi-TKI, targeting the RON/MET/TAM signalling pathways, may be a more effective therapeutic strategy for the treatment of MPM as opposed to targeting RON alone.