Clinical Outcome and Drug Resistant Biomarkers Establish for Hpv Infected Non-Small Cell Lung Cancer

Lung cancer is leading cause of cancer death in Taiwan. The 5-year survival rate in lung cancer patients remains ~15% during the past three decades. Therefore, dissolving tumor recurrence and drug resistance is urgently needed for improving outcome in lung cancer, especially in nonsmokers. Previous reports showed that HPV16/18 infection involved in non-smoking female lung cancer progression in Taiwan. Previous studies showed that HPV involved in drug resistant of lung cancer is partially mediated through regulated IL-6, Mcl-1, DDX3, p21, hTERT, cIAP2, FOXM1, and LKB1expression. However, changes of these genes could not be monitored in blood. Previous reports showed that miRNAs in blood could be used as biomarkers for early diagnosis and predict clinical outcome of lung cancer. Our preliminary data showed that miR-30c-2* levels were elevated 45-fold in E6-knockdown TL-1 cells as compared with parental cells with non-specific RNAi transfection. Moreover, the expression levels of miR-30c-2* in tumor tissues were consistent with in blood could be used to predict survival of lung cancer patients. Thus, we hypothesis changes of miRNAs could be used to evaluate the clinical outcome the therapeutic response of lung cancer patients. In this three years project, the human specimen, primary culture cells, and animal model will be used to verify whether target miRNAs regulated by E6 could contribute to tumor recurrence and drug resistance. First year: 20 up- and 20 down-regulated HPV associated target miRNAs from microarray data will be analyzed in tumor tissues and paired blood samples of lung cancer patients. The clinical specimen will be used to understand whether the expression levels of target miRNAs are correlated with HPV infection and whether the expression levels of target miRNAs could be associated with tumor recurrence, clinical outcome and therapeutic response in lung cancer patients. Whether the expression levels of target miRNAs in patients’ blood are consistent with in tumor tissues and could be associated with survival and therapeutic response in lung cancer patients with cisplatin-based chemotherapy or TKI-targeting therapy. Second year: E6-positive TL-1, –negative TL-4, and lung cancer cells with different p53, k-ras, and EGFR status cultured from lung cancer patients will be treated by cisplatin-based chemotherapy or TKI-targeting drugs. The changes of target miRNAs in the cells will be analyzed and the results will be compared with the first year project. The goal of this year is to establish the biomarkers to monitor the drug response. Third year: The xenograft animal model will perform to establish personalize therapy based on the changes of miRNAs. The results obtained from this project will help us to find the biomarkers for clinical diagnosis and therapy and provided evidence for personalize medicine, especially in drug resistant of HPV+ lung cancer patients. This could offer new therapeutic strategy to improve the outcome in lung cancer, especially in patients with HPV-infection.