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I. Opitz



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    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.05 - Intracavitary Cisplatin-Fibrin Chemotherapy after Resection for Malignant Pleural Mesothelioma Patients (INFLuenCe-Meso) - preliminary results (ID 2683)

      10:50 - 10:55  |  Author(s): I. Opitz

      • Abstract
      • Presentation
      • Slides

      Background
      Local mesothelioma recurrence remains a challenge even after multimodal therapy. Intracavitary chemotherapy is a promising approach to improve local tumor control. In preclinical studies we observed improved pharmacokinetic characteristics when cisplatin was loaded to a fibrin carrier and applied to the chest wall after surgery while effectiveness remained the same compared to cisplatin applied as a solution. We will present the first results of a phase I –dose-escalation-clinical study.

      Methods
      Since 11/2012 3 patients were included in the study. Cisplatin-fibrin was applied after pleurectomy/decortication (P/D) to the chest wall in a concentration of 11 mg/m[2] BSA. Blood samples were taken at several time points after the application (2, 6, 10, 24, 48 and 120 hours) to assess serum cisplatin levels and to test toxicity in the early phase until 14 days postoperatively. The concentration of total platinum was quantified by means of inductively coupled plasma sector field mass spectrometric detection. Adverse events were graded according to the CTCAE.

      Results
      Between November 2012 and March 2013 three patients (2x epithelioid, 1x biphasic) in stage II, III and stage IV were included and received P/D plus Cisplatin-Fibrin in a concentration of 11 mg/m[2]. The maximum concentration of cisplatin in the serum was below 0.3 µg/g at 2 h after application and continued to decrease over a period of 5 days (see image 1). No severe adverse events were observed. The adverse events documented were not related to cisplatin (table 1):

      Diagnosis / symptoms CTC AE grading Number of patients Related to Cisplatin
      Fatigue Grade II 2 possible
      Anemia Grade III 2 unlikely
      Nausea / vomiting Grade I 1 possible
      Increased kreatinin & urea levels Grade II 1 possible
      Increased CK levels Grade IV 1 unlikely
      Increased level of transaminases Grade III 1 unlikely
      Urinary retention Grade II 1 unlikely
      Hypotension Grade II 1 unlikely
      Pneumothorax Grade II 1 unlikely
      Figure 1

      Conclusion
      Our preliminary results show, that cisplatin-fibrin application to the chest wall and the lung surface after P/D is safe on a dose level of 11mg/m2 BSA. As no treatment related mortality and no drug related toxicity was observed we escalate the dosage to 22 mg/m2 BSA, further results including chest wall concentrations of cisplatin will be available in October.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-055 - The RON (MST1R)/MSP pathway is a potential therapeutic target in malignant plural mesothelioma (ID 3250)

      09:30 - 09:30  |  Author(s): I. Opitz

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. Treatment options are limited and drug resistance is common. Thus, there is a need to identify novel therapeutic targets in this disease in order to improve treatment options and survival times. Macrophage stimulating protein (MSP) is the only ligand recognised to bind to the RON receptor (MST1R). RON is a member of the MET proto-oncogene family. The MSP-RON signalling pathway has been implicated in a variety of cellular functions such as macrophage morphogenesis and phagocytosis. De-regulation of this pathway has been linked to tumour progression and metastasis in a number of cancers. We have previously identified RON as frequently activated in MPM and high positivity for RON by IHC was an independent predictor of favourable prognosis.

      Methods
      A panel of mesothelioma cell lines were screened for the expression of MSP and RON at the mRNA (RT-PCR) and protein (Western blot) level. The effect of MSP, IMC-RON8 (a humanised IgG1 monoclonal antibody), LCRF004 (a small molecule inhibitor) and NRWHE (a small peptide) was examined in the H226 cell line using proliferation (BrdU ELISA), apoptosis (Multi-parameter apoptosis assay) and migration assays (xCELLigence). A phospho-kinase proteome profiler array was utilised to detect the downstream signalling pathways activated upon MSP stimulation. The expression of MSP and the macrophage marker, CD-68, was examined by IHC using MPM TMAs. Studies are ongoing to determine the effect of the LCRF004 compound in vivo using a xenograft murine model with the H226 cells.

      Results
      The mRNA and protein levels of RON and MSP were differentially expressed in a panel of MPM cell lines. Treatment with LCRF004 resulted in significantly decreased proliferation and increased apoptosis in the H226 cells. MSP was unable to rescue the cells from the effects of LCRF004. NRWHE and RON8 had little effect on either proliferation or apoptosis. All of the compounds examined inhibited the migration capacity of the H226 cells. The combination of LCRF004 and MSP produced a synergistic effect, showing greater inhibition of migration than either compound alone. However, MSP treatment resulted in the up-regulation of a number of phosphor-kinases including Akt, ERK and the Src family. Currently, a number of proteins identified in the array studies are undergoing validation. Results of an in vivo H226 murine model using the LCRF004 compound will be presented at the meeting.

      Conclusion
      From previous work performed in this laboratory, we have determined that high expression of RON in MPM is an independent predictor of favourable prognosis. IHC was performed on a TMA of MPM patient samples and high expression levels of MSP correlated with better survival. There was no association between CD68 staining and MSP, nor correlation of CD68 expression with survival. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM. The seemingly counter intuitive results obtained from the MPM TMA studies and the in vitro experimental data, may be RON isoform dependant. Additional studies are ongoing to further delineate the RON-MSP axis in MPM.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-020 - Prognostic Markers for Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural pneumonectomy (ID 1879)

      09:30 - 09:30  |  Author(s): I. Opitz

      • Abstract

      Background
      Multimodal treatment provides the best outcome for some but not all malignant pleural mesothelioma (MPM) patients. Therefore the identification of prognostic markers helping to select patients remains a subject of key importance. Frequent loss of NF2 tumor suppressor gene, a regulator of Hippo pathway and mammalian target of rapamycin (mTOR) has been well documented in MPM. We recently observed loss of expression of phosphatase and tensin homologue (PTEN), a tumor suppressor gene of the phosphatidylinositol 3-kinase (PI3K)/mTOR pathway, in 62% of MPM patients. In this regard, increased activity of these pathways stemming from loss of abovementioned tumor suppressor genes may serve as potential prognosticator as well as therapeutic target. Here we aim to assess prognostic significance of PI3K/mTOR and Hippo pathways for MPM patients treated with a multimodal approach.

      Methods
      Large cohort of MPM patients uniformly treated with induction chemotherapy followed by extrapleural pneumonectomy was employed in this study. Tissue micro arrays were constructed composing of paired samples from patients (n = 153) collected pre- and post-induction chemotherapy. All tissues were evaluated for apoptotic index (cleaved caspase-3) and proliferation index (Ki-67). Expression levels of biomarkers of PI3K/mTOR (PTEN, p(phosphorylated)-mTOR and p-S6) and Hippo signaling pathway (nuclear-YAP and nuclear-Survivin) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression free survival (PFS).

      Results
      Survival analysis showed that high p-S6 expression and high Ki-67 index in samples of treatment naïve patients was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 index after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples prior and post induction chemotherapy revealed that decreased cytoplasmic PTEN as well as increased p-mTOR expression was associated with a worse OAS (p = 0.04 and 0.03, respectively). No correlation was observed between expression level of nuclear-YAP with PFS or OAS.

      Conclusion
      Ki-67 proliferation index has prognostic value for MPM patients treated with multimodality approach in when analyzed both pre- and post- induction chemotherapy specimens. Our results further reveal the prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy. If confirmed, these data suggest PI3K/mTOR pathway to be a target for selected MPM patients.