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N. Van Zandwijk



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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-006 - Targeted delivery of RRM1-specific siRNA leads to tumour growth inhibition in malignant pleural mesothelioma (ID 1508)

      09:30 - 16:30  |  Author(s): N. Van Zandwijk

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy with poor prognosis. MPM is typically recalcitrant to treatment and new therapies are urgently needed. Multiple genes involved in proliferation and metabolic activity are upregulated in MPM and these represent attractive targets for an siRNA-based therapeutic intervention.

      Methods
      We carried out an RNAi-based screen of 40 target genes previously shown to be upregulated in MPM to identify candidate genes with roles in cell growth and survival in MPM cell lines. Effects of target gene silencing were measured using standard in vitro proliferation assays. Lead candidates were further assessed with siRNA dose response experiments. The specificity of siRNA-mediated growth inhibition was confirmed by assessing gene knockdown by real-time qPCR and Western blotting. The effects of the most potent siRNAs on xenograft tumour growth were assessed in vivo by delivery using EGFR-targeted, siRNA-loaded, minicells.

      Results
      All 40 genes were effectively silenced, and for 6 genes (PLK1, CDK1, NDC80, RRM1, RRM2 and BIRC5) knockdown with 2 independent siRNAs resulted in significant growth inhibition over time in multiple cell lines. Dose response experiments revealed that siRNAs specific for RRM1 and RRM2 were the most effective at inhibiting growth with IC50 values in the low nanomolar range. Intravenous administration of RRM1 siRNA packaged in minicells targeted with EGFR-specific antibodies (2x10[9] minicells per dose, 4 times per week for 3 weeks) led to consistent and dose-dependent inhibition of MPM tumor growth compared with treatment with an inactive siRNA. Reducing the dose and number of administrations did not reduce growth inhibition; as little as 1x10[9] minicells administered once a week were sufficient to completely inhibit MPM tumour growth.

      Conclusion
      RRM1 is an attractive target for siRNA-based inhibition, and siRNA delivery with EGFR-targeted minicells represents a novel therapeutic approach for MPM.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-010 - Estimation of an optimal chemotherapy utilisation rate for malignant pleural mesothelioma: An evidence-based benchmark for patient care (ID 2535)

      09:30 - 16:30  |  Author(s): N. Van Zandwijk

      • Abstract

      Background
      Chemotherapy has been shown to provide a survival benefit in malignant pleural mesothelioma (MPM). There are wide ranging chemotherapy utilisation rates internationally (18 – 61%). This study aims to determine the optimal proportion of patients with MPM that should receive chemotherapy at least once during the course of their illness, based on the best available evidence, so that it can be determined whether chemotherapy is under-utilised in MPM.

      Methods
      An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Epidemiological data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated (resectability of the tumour, degree of comorbidities and patient performance status) were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate, using the decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the overall utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation in the literature.

      Results
      Chemotherapy is recommended at least once in 65% of all MPM patients. Sensitivity analyses indicate an optimal utilisation rate ranging from 50 to 65% for at least once during the course of their illness. The optimal utilisation rate is consistently higher than the reported actual chemotherapy utilisation rates in United Kingdom (18%), Netherlands (36%), United States (37%), and Australia (54%).

      Conclusion
      An evidence-based model provided an optimal chemotherapy utilisation rate for patients with MPM of 65%. It can serve as a feasible measure of the quality of cancer care. Chemotherapy appears to be under-utilised in the management of MPM in a number of high-income countries.