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N. Pavlakis



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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.08 - Identifying Strategies For The Treatment Of Acquired EGFR Tyrosine Kinase Inhibitor Resistance (ID 3187)

      11:05 - 11:10  |  Author(s): N. Pavlakis

      • Abstract
      • Presentation
      • Slides

      Background
      The management of non-small cell lung cancer (NSCLC) is becoming increasingly personalised with the identification of oncogenic drivers of cancer cell growth which are able to be targeted therapeutically. The paradigm of advanced non-squamous NSCLC treatment now incorporates assessment of epidermal growth factor (EGFR) mutations and treatment with EGFR tyrosine kinase inhibitors (TKIs) in cases where sensitising mutations are found, which results in significant prolongation of progression-free survival compared to empirical chemotherapy. However, the emergence of acquired resistance to EGFR TKIs is almost universal and the two most common mechanisms of resistance include the acquisition of a second mutation in EGFR, the T790M mutation, and c-MET amplification. Approximately one-quarter of cases of resistance are yet to be defined mechanistically and furthermore, optimal subsequent treatment remains unknown. Further research is required to understand the molecular origins of the development of acquired resistance in order to develop rational treatment strategies that incorporate both targeted and cytotoxic therapies. This study is evaluating, using in vitro models, pathways involved in the development of acquired resistance to EGFR TKI and chemotherapy and evaluating critical differences according to EGFR mutation status.

      Methods
      A panel of human NSCLC cell lines with varying clinically relevant molecular characteristics is being assessed and used to develop resistance to various cytotoxic agents and EGFR TKIs, through chronic low dose exposure, as outlined in the table below:

      Cell Line Mutation Status EGFR TKI Sensitivity Resistant Cell Line Generated
      HCC827 EGFR Exon 19 deletion Sensitive Erlotinib; Cisplatin; Paclitaxel; Pemetrexed
      H1975 EGFR Exon 21 Point Mutation (L858R) and T790M mutation Resistant Cisplatin; Paclitaxel; Pemetrexed
      H1299 EGFR Wild-Type Resistant Cisplatin; Paclitaxel; Pemetrexed
      A549 EGFR Wild-Type and KRAS Mutation Resistant Cisplatin; Paclitaxel; Pemetrexed, HDAC-inhibitor
      Assessments of proliferation, cytotoxicity and key signalling pathways are being conducted to evaluate mechanisms of chemotherapeutic and targeted therapy resistance.

      Results
      Chronic low dose exposure has been successful in generating resistant cell lines to both chemotherapeutic agents and the EGFR TKI erlotinib. Cross-resistance to taxol in cisplatin-resistant cell lines has been observed, along with evidence of epithelial-to-mesenchymal transition in the development of EGFR TKI resistance. Antibody arrays of key signalling pathways are being conducted to confirm critical pathways of interest.

      Conclusion
      The panel of human NSCLC cell lines with parental lines harbouring various EGFR sensitising and resistance mutations and generated lines resistant to cytotoxic agents and EGFR TKI are a useful in vitro model to understand key pathways involved in the emergence of therapeutic resistance and to understand how both sensitising and resistant EGFR mutations influence response to cytotoxic agents. This will guide treatment strategies selected for evaluation in vivo that may influence future treatment selection for patients.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-046 - ROS1 overexpression by immunohistochemistry in non-small cell lung cancer: clinical characteristics, natural history and potential new therapeutic target based on two Australian cases (ID 3081)

      09:30 - 09:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Recent years have seen worldwide interest in the study of driver mutations in lung cancer, in particular epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase gene rearrangement (ALK). ROS1 gene rearrangement is a recently identified driver mutation and potential therapeutic target for crizotinib and similar agents. However little is known of the natural history of patients with ROS1, and moreover the diagnostic value of immunohistochemistry (IHC) compared to fluorescent in-situ hybridization (FISH).

      Methods
      12 patients from a single Australian tertiary institution with advanced non-small cell lung cancer (NSCLC) were screened for ROS1 overexpression and gene rearrangement. Selection was based on negative testing for EGFR and ALK, and unusually long natural history.

      Results
      We report 2 patients with ROS1 overexpressed advanced NSCLC, their unique characteristics, long natural history and the use of IHC as a complementary method to FISH in identifying these patients. Mr GL was a 62 year-old Caucasian man and lifelong non-smoker who presented with an incidental 19mm subpleural left lower lobe lung nodule found on computed tomography (CT) when he was treated for pneumonia in 2008. He was monitored with CT for his pulmonary nodule and pre-existing interstitial lung disease. In 2011, CT and subsequent positron emission tomography (PET) showed new regional lymphadenopathy and widespread sclerotic bone disease with the pulmonary nodule unchanged in size but moderately glucose avid. Axillary and supraclavicular lymph node biopsies confirmed metastatic adenocarcinoma consistent with a lung primary. EGFR and ALK testing was negative. He received induction and maintenance chemotherapy until disease progression in 2013. His original biopsy tested negative for ROS1 rearrangement by FISH but stained strongly positive for ROS1 overexpression by IHC using the Epitomics rabbit monoclonal antibody (D4D6) with diffuse cytoplasmic positivity. He was commenced on crizotinib, achieving and maintaining stable disease after three months. Mrs MM was a 54 year-old Caucasian woman and lifelong non-smoker who presented with an incidental 26mm right lower lobe lung nodule found on CT when she presented with left sided chest pain in 2009. PET and endobronchial biopsy of mediastinal lymph nodes confirmed stage IIIA lung adenocarcinoma. EGFR and ALK testing was negative. She received neo-adjuvant chemotherapy, followed by right lower lobectomy and post-operative radiotherapy. In 2010 she developed right supraclavicular lymph node recurrence and achieved radiological complete response after radiotherapy. In 2011 she developed another isolated nodal recurrence in the right supraclavicular fossa, which was surgically resected and confirmed adenocarcinoma. It stained strongly positive for ROS1 overexpression by IHC and positive for ROS1 rearrangement by FISH. In 2013, PET found an isolated hepatic metastasis. She was commenced on crizotinib with plans for re-staging and consideration for liver directed therapy. Clinical progress of the patients will be updated and presented.

      Conclusion
      Our cases of ROS1 overexpressed NSCLC illustrate unique patient characteristics of never-smoking status, adenocarcinoma histology, negative testing for EGFR and ALK, and an unusually long natural history. Our cases highlight the need for greater understanding of the predictive value of ROS1 overexpression by IHC as opposed to FISH alone for targeted therapy.