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Z.G. Zimling



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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-021 - Is RRM1 a predictive marker for vinorelbine efficacy - the results from a cohort of malignant pleural mesotheliomas treated with cisplatin and vinorelbine. (ID 3104)

      09:30 - 09:30  |  Author(s): Z.G. Zimling

      • Abstract

      Background
      In a recently published study our group proposes a possible predictive impact of immunohistochemically detected RRM1 on vinorelbine efficacy in advanced NSCLC. This thesis was based on results from a randomized phase III trial comparing triplet-chemotherapy (paclitaxel, cisplatin, gemcitabine) to standard doublet-therapy (cisplatin, vinorelbine). We found that increased expression of RRM1 was associated with significantly decreased progression-free survival (PFS) and overall survival (OS) only in the patients receiving cisplatin-vinorelbine therapy. These findings were suprising since the overexpression of RRM1 is conventionally associated with resistance towards the chemotherapeutic agent gemcitabine, which is a potent inhibitor of ribonucleotide reductase (RNR). RNR is an essential enzyme for DNA synthesis that converts ribonucleoside di-phosphates into deoxyribonucleoside di-phosphates. The enzyme consists of a large sub-unit (RRM1) and a small sub-unit (RRM2). Vinorelbine is a spindle-poison and resistance towards this agent has never been associated with RRM1 over-expression. It has however been shown that vinorelbine can reduce the repair of radiotherapy-induced DNA damage in small-cell lung-cancer cell-lines, pointing to a possible interaction between vinorelbine and the DNA repair system. This study aimed at further exploring the possible predictive value of immunohistochemically detected RRM1 in patients receiving vinorelbine therapy. For this purpose we chose a cohort of malignant pleural mesothelioma patients treated with cisplatin and vinorelbine in a phase II trial.

      Methods
      Fifty-four consecutive patients with MPM, were enrolled between February 2003 and September 2006 into a phase II trial with cisplatin and vinorelbine. The formalin-fixed paraffin-embedded bioptic tumor specimens from these MPM patients were retrospectively evaluated for RRM1 expression by immunohistochemistry (IHC) using an H-score. The cut-off point was chosen as the upper quartile value of the H-scores to separate positive (H-score ≥upper quartile) from negative (H-score

      Results
      Sixty-six patients had enough tumor tissue for IHC. The upper quartile H-score was 3 yielding 15 positive and 34 (69%) negative tumors in the cisplatin-vinorelbine treated group. In the carboplatin-pemetrexed treated group there were 6 positive and 11 (64%) negative tumors. There was a significant overall survival advantage only in the RRM1-negative patients treated with cisplatin and vinorelbine (log rank p= 0.002). This group had a two-year survival rate of 47% opposed to 13 % for the RRM1-positive tumors treated with this combination. In the carboplatin-pemetrexed-treated group there were no differences in overall survival according to marker status, with two-year survival rates of 0% and 9% in the RRM1-positive and –negative group respectively.

      Conclusion
      Patients with RRM1-negative tumors treated with cisplatin-vinorelbine combination therapy had a prolonged overall survival. There was no survival advantage in the RRM1-negative group when patients were treated with carboplatin and pemetrexed. Our study suggest a possible role of RRM1 in predicting efficacy of cisplatin-vinorelbine combination chemotherapy ,also in MPM, which supports the similar finding from our group in NSCLC patients. Thus, RRM1 may be a biomarker for vinorelbine though the results require further validation.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-021 - Targeting HDACs to overcome cisplatin resistance in malignant plural mesothelioma (ID 3207)

      09:30 - 09:30  |  Author(s): Z.G. Zimling

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive cancer of the mesothelial cells and is becoming a worldwide health burden. Progress in the treatment of MPM remains difficult, underscored by the fact that no single treatment option has proven particularly effective and chemo-resistance is a common problem. However, epigenetic modifiers, such as histone deacetylase inhibitors (HDi) have emerged as a novel class of anti-cancer agent and are currently undergoing clinical trials in numerous cancers. There is also evidence to suggest that HDAC expression may play a role in the development of chemo-resistance. We investigated the levels of HDACs in MPM cell lines, patient samples and determined the effect of HDi on MPM cisplatin sensitive and resistant cell lines.

      Methods
      A panel of MPM cell lines (n=16) was screened for the expression of HDAC11, Class I (HDAC1/2/3/8) and Class II (HDAC4/5/6/7/9/10) HDACs at the mRNA level (RT-PCR) and at the protein level (Western Blot). The HDAC expression profile was determined in an isogenic cell line model consisting of a cisplatin sensitive (Parent) and resistant (CisR) MPM cell line, P31. In addition, HDAC expression was examined in panel of twenty patient samples (benign/biphasic/sarcomatoid/epithelial). Also, MPM TMAs were stained by imummo-histochemistry for HDAC5 expression. Furthermore proliferation assays (BrdU ELISA) were performed to determine the effect of two HDi on the p31 cell lines. The HDi used were Vorinostat (pan HDAC inhibitor) and 19i (selective HDAC5 inhibitor).

      Results
      HDAC11, Class I and II HDACs were detected to varying degrees at the mRNA and protein level within our cell line panel. In the P31 isogenic parent/cisplatin resistant, HDAC protein expression was decreased (HDAC2/3/4/5/7) in the CisR compared with the Parent. HDAC5 was significantly reduced at both the protein and the mRNA level (p<0.05). The expression of HDACs 1/2/3/5 were increased in the MPM patient samples (n=15) compared with benign (n=5) (HDAC2/3/5, p<0.05). HDAC5 staining in a cohort of MPM samples, demonstrated no significant association between survival and a low HDAC5 score. However females had a greater median survival than their male counterparts. Vorinostat and 19i significantly reduced the proliferative capacity of the p31 Parent and CisR. SAHA was more effective in the Parent cells compared with CisR. The effect of 19i was similar in both cell lines.

      Conclusion
      Altered HDAC expression was observed in an isogenic Parent and CisR MPM cell model. Work ongoing in non-small cell lung cancer (NSCLC) has also demonstrated significantly reduced HDAC5 levels in CisR compared with Parent. This may suggest that a reduction in HDAC expression is involved in cisplatin resistance. Reduced levels of HDAC5, in an MPM TMA, were not associated with survival. It should be noted, however that patient numbers were small and biphasic and sarcomatoid sub-types had the lowest expression levels of HDAC5. We are currently increasing our patient numbers for an additional IHC study. HDi significantly reduced the proliferative capacity of CisR and Parent MPM cells. HDAC levels may represent an important biomarker in stratifying patients for future epigenetic targeted therapies in MPM.