Thesis (M.S.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains vii, 53 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 48-53).

Oncogenic mutations in lung cancer further our knowledge about cancer initiation and progression, and may guide personalized treatment. The fact that targeted therapy is most effective in subsets of patients with defined molecular targets indicates the need for classification of clinically-related molecular tumor phenotypes based on the presence of oncogenic mutations, including EGFR mutations and EML4-ALK rearrangements. The identification of EGFR mutations, in up to half of lung adenocarcinomas in Asians, could predict clinical sensitivity to tyrosine kinase inhibitor (TKI). However, testing for mutations is not always possible due to tumor tissue availability. The therapeutic decision sometimes remains a clinical one especially for elderly lung cancer patients but no known mutation status. We studied the survival outcomes of targeted therapy versus conventional chemotherapy in elderly patients with lung cancer when we did not yet have routine EGFR mutation testing and demonstrated comparable survival outcomes in targeted therapy compared to chemotherapy, implying that survival with targeted therapy could be better if the treatment population could be selected with EGFR mutations. Though testing for EGFR mutation in tumor biopsy have later become routine practice and remains the accepted reference for therapeutic decision, the detection of EGFR mutations in plasma DNA with high diagnostic performance will be useful adjunct for diagnostic and therapeutic monitoring. Among patients with EGFR mutations in tumor biopsy, the concurrent detection of EGFR mutation in plasma DNA was found to confer a less favorable prognosis in terms of overall survival than those patients with EGFR mutations in tumor biopsy but the corresponding mutation was not detected in plasma. Other oncogenic mutations with therapeutic implications in lung tumors are yet to be fully explored, like ALK, KRAS, ROS1 or NTRK1 mutations. It is not exactly the tumor – but the mutations in the tumor that need to be explored with reference to clinical behavior. Even with EGFR mutation with well-established clinical implications, further exploration into its mechanistic functions will help in understanding of drug resistance. Lung cancer cell lines established from patients with known mutation profiles could be useful tools for studying the biology of known molecular targets as well as for therapeutic testing. Four new lung adenocarcinoma and one mesothelioma cell lines were established from patients with different clinical characteristics and oncogenic mutation profiles. These cell lines with defined mutation profiles will provide tools for exploration of lung cancer and mesothelioma biology with respect to molecular therapeutic targets. The Large Tumor Suppressor 2 (LATS2) gene was a differentially expressed gene between EGFR mutant and wildtype lung adenocarcinomas. The differential LATS2 expression levels were predictive of survival in patients with resected lung AD and may modulate tumor growth via different signaling pathways in EGFR mutant and wild-type tumors. The identification of oncogenic mutations has led to a new paradigm of targeted therapy in lung cancer. Further improvements in outcome of lung cancer management will stem from research into the biology of oncogenic mutations and their clinico-pathological correlations, which would fuel parallel development of clinically efficacious targeted therapies. / published_or_final_version / Medicine / Master / Doctor of Medicine

Non-small cell lung cancer (NSCLC) causes most of the cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs), like erlotinib and crizotinib, are commonly used as specific treatments targeting epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Autophagy is a highly conserved cellular process in response to stress. Tumor microenvironment (TME) is composed of both tumor cells and stromal cells. This study aimed to investigate whether autophagy could confer intrinsic and acquired resistance to TKIs in NSCLC, and its role in the presence of TME or in animal models. In the first part of this study, the effect of EGFR TKI or ALK TKI on sensitive NSCLC cells to generate autophagy was investigated, and manipulation of autophagy in these cell lines was performed. Autophagy inhibition was shown to enhance apoptotic effect of TKIs in sensitive NSCLC cells. This part provided strong evidence that TKIs and autophagy inhibitor chloroquine (CQ) work synergistically in sensitive NSCLC cells. Autophagy induction by erlotinib treatment was observed in a HCC827 (lung adenocarcinoma, EGFR exon 19 del) xenograft model, which was in line with the in vitro observation. Correspondingly, the combination of erlotinib (12.5 mg/kg) with CQ (50 mg/kg) in the HCC827 xenograft model achieved greater tumor growth suppression, compared with single drug treatments. In the second part of this study, a model of TME was established to allow study of autophagy under such circumstances. An activated TME with cytokine production, autophagy induction and epithelial-to-mesenchymal transition (EMT) was generated by co-culturing NSCLC cells and human fibroblasts. Sensitivity to TKI under TME was not affected, and combination of chloroquine with TKI under TME remained synergistic compared with single treatments. In the third part of this study, erlotinib-resistant (ER) HCC827 cells were acquired by stepwise exposure to increasing concentrations of erlotinib in cell culture. Common acquired resistance mechanisms to EGFR TKI (EGFR T790M or c-MET amplification) were excluded in this ER HCC827 model, except EMT. Autophagy status in ER HCC827 cells was studied and autophagy manipulation was performed. It was found that CQ and erlotinib worked synergistically to induce cell death even in ER HCC827 cells. In an ER HCC827 xenograft model, significant degree of autophagy and EMT was evident. Interestingly, combining erlotinib (25 mg/kg) with CQ (50 mg/kg) showed better inhibitory effect on tumor growth compared with single treatments. In summary, TKIs induced both apoptosis and autophagy in EGFR-mutated and ALK-rearranged NSCLC cells. Autophagy inhibition by CQ enhanced TKI-induced cell death in sensitive cells. The presence of TME did not confer TKI resistance. Autophagy was highly activated in EGFR-mutated NSCLC cells with acquired resistance to erlotinib. Combination of CQ with erlotinib remained synergistic in the presence of TME and acquired resistance, both in vitro and in vivo. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

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Thesis (Ph. D.)--State University of New York at Binghamton, Department of Computer Science, 2006. / Includes bibliographical references (leaves 199-204).

Thesis (M. Sc. Med.)--University of Sydney, 2008. / Title from title screen (viewed 29 July 2008). Submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2008; thesis submitted 2007. Includes bibliographical references. Also available in print form.

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Bibliography: leaves 118-142. Also available online.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (Ph. D.)--University of Hawaii at Manoa, 2003. / Includes bibliographical references (leaves 95-113).