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Q. Zhou



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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.08 - Individualized Surgical Treatment for Locally Advanced Non-small Cell Lung Cancer Based on Molecular Biomarkers. (ID 2314)

      16:15 - 17:45  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background
      Approximately 35%-40% of NSCLC have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy and radiotherapy. The aim of this study is to explore and summarize the probability of molecular biomarker detection in cancer tissues, mediastinal lymph nodes and peripheral blood for molecular stages and types of lung cancer, and for individual surgical treatment and postoperative adjuvant therapy and for prediction of postoperative recurrence of lung cancer in stage III disease; to summarize the long-time survival result of personalized surgical treatment of 1036 patients with LANSCLC based on molecular biomarker detection.

      Methods
      CK19 and Muc-1 mRNA expression of peripheral blood was detected in 1036 patients by RT-PCR before and after operation for individual molecular staging and personalized surgical treatment and postoperative adjuvant therapy. micro-RNA and gene chips were used to detect the differential micro-RNAs and gene profiles between the primary cancer tissues and metastatic mediastianl lymph nodes for individual postoperative adjuvant therapy and prediction of prognosis of the patients with LANSCLC. The long-term survival of personalized surgical treatment was retrospectively analyzed in the 1036 patients based on molecular staging and typing.

      Results
      There were 678 squamous cell carcinoma and 358 adenocarcinoma. 212 patients had IIIA disease and 824 had IIIB disease according to P-TNM staging. 126 patients had M-IIIA disease, 603 had M-IIIB disease and 307 had M-IV disease according to molecular staging. Of the 1036 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 356 cases; double sleeve lobectomy combined with resection and reconstruction of partial left atrium, superior vena cava, carina, aorta and postcava was performed in 680 cases in this series. Thirteen patients died of operative complications and the operative mortality was 1.16%. CK19 and Muc-1 mRNA positive expression in peripheral blood was found in 265(25.6%) patients. The differential micro-RNAs and gene profiles between the primary cancer and metastatic mediastinal lymph nodes divide the 1036 patients into high and low recurrence risk groups. The median survival time was 51.74 months. The 1, 3, 5 and 10 year survival rates of the 1036 cases was 81.1%, 49.3%, 30.8% and 21.4%, respectively.The postoperative survival rate was remarkably correlated with individual molecular staging and typing, micrometastasis, histological classification and size of primary cancer and LN metastasis (P<0.05). Multivariable Cox model analysis showed that “personalized molecular staging”, micrometastasis, the differential micro-RNAs and gene profiles and mediastinal lymph node metastasis were the most significant factors for predicting prognosis in the patients with LANSCLC.

      Conclusion
      Detection of micrometastasis in peripheral blood will be helpful for individual surgical treatment and postoperative adjuvant therapy in LANSCLC patients. The differential micro-RNAs and gene profiles can predict the recurrence and prognosis of the cancer. Individualized surgical treatment can significantly improve prognosis and increase curative rate and long-term survival rate of LANSCLC based on personalized molecular staging and typing.

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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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      P1.05-014 - Cancer Stem Cell-like Population from Non-Small Cell Lung Cancer is Preferentially Suppressed by EGFR-TKIs (ID 2099)

      09:30 - 16:30  |  Author(s): Q. Zhou

      • Abstract

      Background
      Lung cancer is the leading cause of death worldwide with a high metastasis and recurrence rate. Non-small cell lung cancer (NSCLC) accounts for 75-85% of lung cancers. Growing evidences show that some, if not all, tumors derive from a minor subpopulation of cancer cells, also known as cancer stem-like cells (CSCs), either retain or acquire the capacity for self-renewal and drug resistance. By the virtue of altered cell signaling pathways related to cell survival and/or apoptosis, CSCs are able to survive radiation or chemotherapeutic insults. Thus, the targeting of key signaling pathway(s) that is active in CSCs is very attractive therapeutic strategy to treating cancers. However, research has been hampered due to the lack of distinct molecular makers on CSCs. We take advantage of a rare subset of cells that can efflux the DNA binding dye out of the cell. These cells, called side population (SP) cells, are proved to be enriched with CSCs and have stem cell characteristics.

      Methods
      The SPs in PC-9 cells ware detected by staining them with Hoechst 33342. CSC population in PC-9 cells, the phosphorylation of EGFR at Tyr1068, AKT at Ser473 and ERK at Thr202/Tyr204 were investigated by FCM after treatment with EGFR/PI3K/AKT signaling inhibitors including Gefitinib, LY294002, U0126 and Erlotinib. significantly reduced the stem-like cancer cells. The effects of over-expression and silencing of β-catenin on the CSC population in PC-9 cells were detected by FCM. The PC-9 transplanted tumor model was used to detect the effects of Gefitinib and Cisplantin on CSC population in PC-9 cells. The Boyden chamber was used to determine the effects of Gefitinib and Cisplntin on the vitro invasion of PC-9 cells.

      Results
      EGFR-TKIs (Gefitinib or Erlotinib) regulate CSC, constitutive activation of EGFR increased the subpopulation almost 4.5-fold to 4.0%. EGFR-TKI almost completely ablated it resulting in only 0.2% or 0.3% of the total cells. EGF promote CSC population, the phosphorylation of EGFR at Tyr1068, AKT at Ser473 and ERK at Thr202/Tyr204 were investigated and they are all positive. EGFR/PI3K/AKT signaling inhibitors including Gefitinib, LY294002, U0126 and Erlotinib, significantly reduced the stem-like cancer cells. A significant decrease in cancer stem-like cells was observed following β-catenin suppression. The treatment with Gefitinib dramatically reduced the tumor numbers and size in vivo xenograft model with PC9 cells. Although there were few SP cells (1.3% as detected) in Gefitinib-treated mice in the primary tumors, more discernible numbers of SP cells were detected in Cisplatin-treated (13.6%) or control-treated tumors (8.3%). Tthe reduction of SP cells by Gefitinib treatment significantly reduced the migration capability of PC-9 cells. As a comparison, those primary culture cells derived from Cisplatin-treated tumors had an increased migration rate.

      Conclusion
      EGFR-TKI can dramatically decrease the CSC population and invasion ability in PC-9 cells in vitro and in vivo. The molecular mechanisms of EGFR-TKI decrease CSCs of lung cancer might be related to that EGFR-TKIs can suppress the Wnt/β-cateninsignal pathway.