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S. Nicholson



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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI08.10 - Co-Occurrence of Driver Mutations of MAPK and PI3K Pathways in Non Small Cell Lung Cancer: A Report from Lung Cancer Genomics Ireland (LCGI) Study (ID 2627)

      16:45 - 18:15  |  Author(s): S. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are frequently altered in human cancers. Targeting these pathways is an attractive therapeutic strategy in malignant disease. The frequency of single and dual pathway alterations varies substantially across various cancers. Co-occurrence of the MAPK and PI3K pathway aberrations is reported in 5-7% of melanomas, gastric and colorectal cancers, and is associated with a worse clinical outcome. In this report we aim to determine the co-occurrence of the MAPK and PI3K pathway mutations in a large cohort of surgically resected NSCLC tumors.

      Methods:
      We used the platform of Sequenom’s MassArray to perform genotyping for 548 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways in surgically resected NSCLC tumors. MAPK pathway genes that were screened include: KRAS, HRAS, BRAF, RAF1, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP2K1, MAP2K2, MAP2K3, and PTPN11. PI3K pathway genes that were screened include: PIK3CA, PIK3R1, PIK3R2, PTEN, PDPK1, AKT1, AKT2, and MTOR. Fisher’s exact test was used to determine the statistical significance of association between the MAPK and PI3K pathway mutations. The strength of association was determined in the form of odds ratio.

      Results:
      NSCLC tumors from 356 patients (258 squamous cell, 98 adenocarcinomas) were tested using Sequenom’s MassArray. The frequency of mutations in the MAPK and PI3K pathways was 22.5% (n=80) and 22.8% (n=81) respectively. Among these patients, 38 patients had mutations in both pathways (i.e: 47.5% of patients with a MAPK pathway mutation also had a mutation in the PI3K pathway, and 46.9% of patients with a PI3K pathway mutation also had a mutation in the MAPK pathway, see table 1). Fisher’s exact test revealed that mutations in the MAPK and the PI3K pathways are mutually inclusive (p<0.0001, odds ratio=4.95, 95% CI 2.9-8.5) Table 1: The co-occurrence of MAPK and PI3K pathway mutations in NSCLC

      Pathway/no of patients PI3K WT PI3K MT
      MAPK WT 235 43
      MAPK MT 42 38


      Conclusion:
      38 (10.7%) of 356 NSCLC patients included in the LCGI study had hotspot somatic mutations in both the MAPK and PI3K pathways. Contrary to previous reports, we observed that activating mutations of the MAPK and PI3K pathways are mutually inclusive in NSCLC. These findings may have implications in designing clinical trials of targeted therapies in lung cancer.

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    MINI 13 - Genetic Alterations and Testing (ID 120)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI13.08 - Targetable Genomic Aberrations in Squamous Cell Lung Cancer (SCC): A Report from the Lung Cancer Genomics Ireland (LCGI) Study (ID 766)

      10:45 - 12:15  |  Author(s): S. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognosis of lung SCC continues to be poor with no molecularly targeted agents specifically developed for its treatment. LCGI aims to identify potential targetable oncogenes in lung SCC.

      Methods:
      The LCGI study is being carried out in 500 patients with surgically resected lung SCC, treated at St James’s University Hospital and Beaumont University Hospital, Dublin. We used the platform of Sequenom’s MassArray to perform genotyping for accustomed panel of 258 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways. We also evaluated FGFR1 amplification by fluorescence in situ hybridization (FISH) and MET protein expression by immunohistochemistry (IHC).

      Results:
      Lung SCCs from 258 patients have been tested by Sequenom MassArray to date. Lung SCCs from 150 patients have been evaluated for MET protein expression and 89 for FGFR1 amplification. 163 (63.2%) patients were male. The median age of the cohort was 68. The majority of patients were either current (39.5%) or former (58.1%) smokers at the time of diagnosis. 138 (53.5%) were stage I, 87 (33.7%) were stage II, and 33 (12.8%) were stage III SCCs. At least one aberrant, potentially targetable oncogene was identified in the SCC of 101 (39.1%) patients (see Table). The presence of PIK3CA or KRAS mutations, or FGFR1 amplification did not have a statistically significant impact on median overall survival or recurrence-free survival. However, the presence of two or more aberrations in driver oncogenes in a tumor (patients, n=19) was associated with a worse median overall survival compared to patients with either a single driver aberration (p=0.04) or no aberrations (p<.01). Table: Frequency of driver mutations in LCGI compared to The Cancer Genome Atlas (TCGA) study

      Mutation LCGI (n=258) TCGA (n=178)
      FGFR1 amp (n=89) 13 % 16.8 %
      PIK3CA 15.1 % 10.1 %
      KRAS 6.5 % 0.6 %
      PTPN11 3.5 % 1.7 %
      STK11 3.1 % 1.7 %
      MYC 1.9 % 0.0 %
      NRAS 1.6 % 0.0 %
      BRAF 1.2 % 3.9 %
      HRAS 1.6 % 1.7 %
      CTNNB1 1.5 % 1.7 %
      FBXW7 1.5 % 3.4 %
      MET Overexpression (n=150) 1.3 % NA
      EGFR 0.9 % 2.8 %
      AKT1 0.4 % 0.6 %
      CDK4 0.4 % 0.0 %
      GNA11 0.4 % 0.6 %
      MAP2K1 0.4 % 0.6 %
      DDR2 0 % 1.1 %


      Conclusion:
      39.1% of lung SCC patients have an aberrant, potentially targetable driver oncogene in their tumor. The presence of two or more aberrant oncogenes is a poor prognostic factor in lung SCC. These findings can be used to guide clinical trials in lung SCC.

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    MINI 34 - RNA and miRNA (ID 162)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI34.07 - A Novel microRNA Signature Associated with Cisplatin Resistance in NSCLC (ID 2709)

      18:30 - 20:00  |  Author(s): S. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs that range in size from 19 to 25 nucleotides. Alteration in miRNA expression can cause them to act as either tumour suppressor or oncogenes. They have also been shown to regulate a number of processes involved in tumour biology such as metastasis, invasion and angiogenesis. More recently, miRNAs have been linked to chemo- and radio-resistance in many solid tumours, including lung cancer.

      Methods:
      An isogenic model of cisplatin resistance was established by chronically exposing a panel of NSCLC cell lines (MOR, H460, A549, SKMES-1, H1299) to cisplatin for 12 months, generating cisplatin resistant (CisR) sublines from their corresponding age-matched parental (PT) cells. MicroRNA expression profiling was carried out using 7th generation miRCURY LNA™ microRNA arrays consisting of 1,919 miRNAs (Exiqon). MicroRNAs that were significantly increased in CisR sublines were inhibited using antagomirs (Exiqon), while those that were significantly decreased were over-expressed using pre-miRs (Ambion). Functional studies examining clonogenic survival ability, proliferation (BrdU) and apoptosis (Annexin V/PI) were subsequently carried out in the presence or absence of cisplatin. To examine the translational relevance of these microRNAs, their expression was further examined in a cohort of pre-treatment matched normal and tumour lung tissues from NSCLC patients of different histological subtypes. Validation of this miRNA signature is currently being investigated in serum samples from this same cohort of patients and normal controls.

      Results:
      MicroRNA profiling analysis identified ten miRNAs which were significantly altered between parental and corresponding cisplatin resistant lung cancer cell lines. Validation of these miRNAs by real-time PCR (qPCR) identified a specific 5-miR signature that was significantly altered in CisR cells relative to their parental counterparts. Modification of these microRNAs altered the response of resistant cells to the cytotoxic effects of cisplatin and decreased the clonogenic survival of CisR cells when treated with increasing doses of cisplatin (0.1µM-10μM). Significant differential expression was found between normal and tumour tissues across each histological subtype, highlighting the potential use of these microRNAs as markers of response to cisplatin therapy in NSCLC patients. Three miRNAs (miR-A, B, C) belonging to the same family were significantly altered in tumour lung tissue of adenocarcinoma and squamous cell histology compared to matched normal lung tissue. MicroRNA-D expression was significantly altered in squamous cell carcinomas while miR-E was differentially expressed in adenocarcinomas only. Data relating to the expression of this novel signature in the circulation of our NSCLC patient cohort and normal controls will be presented at WCLC 2015.

      Conclusion:
      We have identified and validated a novel miRNA signature associated with cisplatin resistance in a panel of cisplatin resistant cell lines and in patient lung tumours. Genetic manipulation of these specific miRNAs in vitro altered the cisplatin resistant cell response to the cytotoxic effects of cisplatin chemotherapy. The data obtained from this study may provide a basis for the potential development of a companion diagnostic for lung cancer patients who are most likely to benefit, or not, from cisplatin chemotherapy.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-057 - Targeting PIM Kinase in NSCLC (ID 933)

      09:30 - 17:00  |  Author(s): S. Nicholson

      • Abstract
      • Slides

      Background:
      PIM proteins belong to a family of serine/threonine kinases composed of 3 isoforms, PIM1, PIM2 and PIM3, that play a key role in cell cycle regulation, have potent anti-apoptotic activity and play a role in the homing and migration of metastatic cells. Furthermore, PIM kinases have also been shown to be activated in response to Akt pathway inhibition, indicating a role in adaptive responses to inhibition of this pathway potentially leading to treatment resistance. Thus, there is a strong rationale for combining PIM kinase inhibition with inhibition of the Akt pathway (i.e., inhibitors of EGFR, PI3K, Akt and mTOR). PIM kinase has been recognised as a therapeutic target particularly in haematological malignancies however the role of PIM kinases in solid tumours and NSCLC in particular are less well characterised. This study is the first to elucidate the expression of all 3 PIM isoforms in NSCLC cell lines and patient tumours as well as to examine the effect of Inflection Bioscience Ltd novel dual PI3K/PIM kinase (IBL-202) and triple PI3K/mTOR/PIM kinase (IBL-301) targeted therapies in-vitro and in-vivo.

      Methods:
      PIM 1/2/3 protein expression was quantified by western blot analysis in a panel of NSCLC cell lines and 40 matched normal/tumour tissues from NSCLC patients (20 adenocarcinoma and 20 squamous cell carcinoma). PIM kinase expression was correlated to patient clinicopathological characteristics and survival data. The effectiveness of IBL-202 and IBL-301 on proliferation and apoptosis in NSCLC cell lines were examined by BrdU and Annexin V/PI FACS analysis, respectively. A head-to-head in-vivo study of IBL-202 vs. IBL-301 in xenograft nude mice formed using H1975 cells is ongoing.

      Results:
      All 3 isoforms of PIM kinase are highly expressed across a panel of NSCLC cell lines. PIM kinase is expressed in ~ 90% of NSCLC tumour tissues across all stages of the disease. IBL-202 and IBL-301 induced apoptosis and decreased cell proliferation in NSCLC cell lines at micromolar concentrations in-vitro. The in-vivo study is ongoing and results will be presented.

      Conclusion:
      PIM kinase is a promising new therapeutic target for the treatment of NSCLC patients. Dual PI3K/PIM kinase (IBL-202) and triple PI3K/mTOR/PIM kinase (IBL-301) targeted therapies have demonstrated pro-apoptotic and anti-proliferative activity in-vitro and in-vivo and should be considered in the treatment of NSCLC patients.

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