Dissertations / Theses on the topic 'Non-small cell lung cancer'
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1
Kapeleris, Joanna C. "Circulating tumour cells in non-small cell lung cancer." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228607/1/Joanna_Kapeleris_Thesis.pdf.
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Circulating tumour cells (CTCs) have the potential to transform the management of patients with non-small cell lung cancer (NSCLC). The applications of CTCs can identify clinically actionable targets to predict treatment response and to better understand metastasis. CTCs isolated using microfluidics can be used as prognostic indicators of NSCLC as well as characterizing for markers of immunotherapy (PD-L1), molecular targets (ALK, EGFR). Short term cultures were successfully expanded in 9/70 NSCLC patients and cultured for up to 3 months. Optimization of this novel CTC culture model provides opportunity to identify new therapeutics for NSCLC patients in a precision medicine approach.
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Sikkink, Stephen K. "Genetic pathology of non-small cell lung cancer." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250405.
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Wong, Wing-sze, and 黃詠詩. "Fusion genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43781378.
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Swinson, Daniel. "Hypoxic markers in non-small cell lung cancer." Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29476.
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Hypoxia is an important factor in the pathogenesis of solid tumours. Hypoxia inducible factors (HIF)-1alpha and HIF-2alpha are transcription factors that in part mediate the cellular response to hypoxia. These transcription factors are involved in the regulation of angiogenesis, anaerobic metabolism, pH homeostasis, erythropoiesis and cell death.;Immunohistochemical (IHC) assays were optimised for HIF-1alpha and one of its transcriptional targets, Carbonic Anhydrase (CA) IX. Attempts to optimise an IHC assay for HIF-2alpha failed to produce reproducible staining. A scoring system was also devised to assess the extent of tumour necrosis (TN) in tumour sections. The expression of these factors was assessed in a retrospective series of patients who had NSCLC tumours resected with curative intent. The expression of EGFR, p53, Bcl-2, MMP-2 and MMP-9 and angiogenesis had previously been assessed.;Extensive TN, perinuclear (p) CA IX and high HIF-1alpha expression were associated with a poor prognosis. PCA IX, stage, gender, MMP-9 and angiogenesis were independent prognostic factors.;The spatial relationship between membranous CA IX expression and TN and tumour microvessels support other studies proposing that CA IX is a marker of tumour hypoxia.;EGFR expression was associated with pCA IX, membranous (m)CA IX and HIF-1alpha expression. In vitro studies demonstrated that prolonged treatment with the EGFR tyrosine kinase inhibitor, ZD 1839 suppressed CA IX expression. These results suggest that activated EGFR may induce CA IX. As such co-expression of these factors may identify patients that are more likely to respond to EGFR targeted therapies.
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Wong, Wing-sze. "Fusion genes in non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43781378.
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Brena, Romulo Martin. "Aberrant DNA methylation in human non-small cell lung cancer." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172083621.
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Brattström, Daniel. "Angiogenesis related markers in non-small cell lung cancer /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl.[distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3558.
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Xinarianos, George. "Genetic alterations in non-small cell lung carcinomas." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343688.
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Brattström, Daniel. "Angiogenesis Related Markers In Non-Small Cell Lung Cancer." Doctoral thesis, Uppsala University, Oncology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3558.
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This thesis investigated the predictive and the prognostic powers of angiogenesis related markers in both operable and inoperable non-small cell lung cancer (NSCLC) patients.
In the first and second study, we investigated the serological fractions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 2 cohorts of patients with either operable or inoperable NSCLC.
Regarding operable NSCLC, we demonstrated significant correlations between VEGF and tumour volume and overall survival. Regarding bFGF, significant correlations with recurrent disease and survival were demonstrated. VEGF and bFGF correlated to each other and with platelet counts. In multivariate analysis, bFGF proved to be a significantly independent prognostic factor.
Regarding inoperable NSCLC, we demonstrated that patients with elevated bFGF levels before any treatment and during chemotherapy had a significantly poorer survival. During chemotherapy, each rise of one unit of bFGF (ng/L) corresponded to a 4 times increased risk of death. Regarding VEGF, elevated levels after radiotherapy corresponded with better survival. All prognostic information demonstrated in this study concerned patients with a, co-sampled, normal platelet count.
In the third study, three putative markers, HER-2, EGFR and COX-2, suitable for targeted therapies in resected NSCLC were investigated in a panel of 53 tumours and further investigated for a possible correlation with microvessel density. We demonstrated that HER-2 and COX-2 were mainly expressed in adenocarcinomas, whereas EGFR was only expressed in squamous cell carcinomas. COX-2 showed a trend towards a correlation with microvesssel density. The expression profile, HER-2+/EGFR-, was significantly correlated to poorer survival.
In the fourth study, a predictive model for recurrences consisting of p53, CD34 and CD105, and circulating serum fractions of VEGF and bFGF, was investigated. The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated. The mutational status could not confirm the immunohistochemical correlation between p53 and recurrences.
In conclusion, the present thesis demonstrates that the angiogenic factors VEGF and bFGF analysed in sera have both predictive and prognostic information when measured in operable and inoperable NSCLC. Since HER-2 is overexpressed in NSCLC and linked with prognostic information, this marker might be a suitable target for therapy in NSCLC. Furthermore, in patients with operable NSCLC, p53 expression status was linked with recurrent disease and mean MVD.
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Lam, Chi-leung David. "Gene expression profiling in non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38585777.
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Ho, Chung-man. "Non-small cell lung cancer from bench to bedside /." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39432592.
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Berrieman, Helen Katherine. "Resistance to chemotherapy in non-small cell lung cancer." Thesis, University of Hull, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415803.
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Ohri, Chandra. "The immune response to non-small cell lung cancer." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/8195.
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Non-small cell lung cancer (NSCLC) is responsible for more deaths worldwide than any other cancer. Currently, 5-year survival for patients with stage IA disease is just 67%. Chemotherapy offers no cure at present for patients with NSCLC. It is now recognised that the immune system plays a significant role in both tumour modulation and progression. Therefore, a better understanding of immune responses to NSCLC may lead to the development of novel therapies. In these studies, I have investigated, using immunohistochemistry, the microlocalisation of macrophage and mast cell phenotypes (as well as mast cell degranulation), TNFα expression, non-macrophage expression of markers associated with macrophage phenotypes, chemokine receptors and markers of apoptosis and cellular proliferation in surgically resected NSCLC tissue. These studies have demonstrated for the first time in NSCLC that there are two major macrophage phenotypes, M1 and M2, and that the cytotoxic M1 phenotype predominates in the islets of patients with extended survival. The presence of high numbers of mast cells in the islets, irrespective of phenotype, also predicts extended survival. In addition, TNFα expression in tumour islets was found to be an independent predictor of increased survival but its expression in tumour stroma was an independent predictor of poor survival. Also, patients with increased tumour islet expression of markers associated with cytotoxic macrophages (HLA-DR, iNOS, MRP 8/14 and TNFα) by non-macrophage cells was associated with extended survival. Patients with increased expression of CXCR3 and CCR1 in their tumour islets also had extended survival suggesting that these chemokine receptors may be involved in a pathway attracting cytotoxic components of the immune system into tumour islets. In summary, these studies highlight the importance of microlocalisation and phenotype of immune cells in determining whether they play a pro- or anti-tumorigenic role in NSCLC.
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Ho, Chung-man, and 何重文. "Non-small cell lung cancer: from bench to bedside." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39432592.
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Lam, Chi-leung David, and 林志良. "Gene expression profiling in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38585777.
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Agrawal, Vishesh. "Quantitative Imaging Analysis of Non-Small Cell Lung Cancer." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27007763.
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Quantitative imaging is a rapidly growing area of interest within the field of bioinformatics and biomarker discovery. Due to the routine nature of medical imaging, there is an abundance of high-quality imaging linked to clinical and genetic data. This data is particularly relevant for cancer patients who receive routine CT imaging for staging and treatment purposes. However, current analysis of tumor imaging is generally limited to two-dimensional diameter measurements and assessment of anatomic disease spread. This conventional tumor-node-metastasis (TNM) staging system stratifies patients to treatment protocols including decisions regarding adjuvant therapy. Recently there have been several studies suggesting that these images contain additional unique information regarding tumor phenotype that can further aid clinical decision-making.
In this study I aimed to develop the predictive capability of medical imaging. I employed the principles of quantitative imaging and applied them to patients with non-small cell lung cancer (NSCLC). Quantitative imaging, also termed radiomics, seeks to extract thousands of imaging data points related to tumor shape, size and texture. These data points can potentially be consolidated to develop a tumor signature in the same way that a tumor might contain a genetic signature corresponding to mutational burden. To accomplish this I applied radiomics analyses to patients with early and late stage NSCLC and tested these for correlation with both histopathological data as well as clinical outcomes.
Patients with both early and late stage NSCLC were assessed. For locally advanced NSCLC (LA-NSCLC), I analyzed patients treated with preoperative chemoradiation followed by surgical resection. To assess early stage NSCLC, I analyzed patients treated with stereotactic body radiation therapy (SBRT). Quantitative imaging features were extracted from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. For patients who underwent SBRT, quantitative features were extracted from cone-beam CTs (CBCT) at multiple time points during therapy. Univariate and multivariate logistic regression were used to determine association with pathologic response. Concordance-index and Kaplan-Meier analyses were applied to time dependent endpoints of overall survival, locoregional recurrence-free and distant metastasis.
In this study, 127 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. 99 SBRT patients were identified in a separate aim of this study. Reduction of CT-defined tumor volume (OR 1.06 [1.02-1.09], p=0.002) as continuous variables per percentage point was associated with pathologic complete response (pCR) and locoregional recurrence (LRR). Conventional response assessment determined by diameter (p=0.213) was not associated with pCR or any survival endpoints. Seven texture features on pre-treatment tumor imaging were associated with worse pathologic outcome (AUC 0.61-0.66). Quantitative assessment of lymph node burden demonstrated that pre-treatment and post-treatment volumes are significantly associated with both OS and LRR (CI 0.62-0.72). Textural analyses of these lymph nodes further identified 3 unique pre-treatment and 7 unique post-treatment features significantly associated with either LRR, DM or OS. Finally early volume change showed associated with overall survival in CBCT scans of early NSCLC.
Quantitative assessment of NSCLC is thus strongly associated with pathologic response and survival endpoints. In contrast, conventional imaging response assessment was not predictive of pathologic response or survival endpoints. This study demonstrates the novel application of radiomics to lymph node texture, CBCT volume and patients undergoing neoadjuvant therapy for NSCLC. These examples highlight the potential within the rapidly growing field of quantitative imaging to better describe tumor phenotype. These results provide evidence to the growing radioimics literature that there is significant association between imaging, pathology and clinical outcomes. Further exploration will allow for more complete models describing tumor imaging phoentype with clinical outcomes.
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Holgersson, Georg. "Prognostic Factors in Non-Small Cell Lung Cancer (NSCLC)." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327925.
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Background: Non-small cell lung cancer (NSCLC) is the cancer disease with the highest mortality globally. About 75% of NSCLC patients are diagnosed in an advanced stage where surgical treatment is not possible. For patients with locally advanced disease without distant metastases, the treatment of choice is curatively intended radiotherapy. However, this treatment has considerable side effects and many patients relapse. To individualize the treatment strategy for these patients, it is essential to have as much prognostic information as possible. The aim of this thesis was to investigate the prognostic significance of histology and pre-treatment hematopoietic blood parameters. Material and Methods: Data were collected retrospectively for NSCLC patients treated between 1990 and 2000 with curatively intended radiotherapy. The data were obtained by manually searching patient records from all radiation oncology departments in Sweden. The prognostic significance of histology, and pre-treatment levels of hemoglobin (Hgb), white blood cells (WBC) and platelets (Plt) were analyzed in relation to overall survival using univariate and multivariate statistical methods. These prognostic factors were further analyzed in a chemoradiation patient cohort and in a cohort of patients with recurrent NSCLC treated with palliative docetaxel, or the insulin-like growth factor 1 receptor (IGF-1R) modulator AXL1717. Results: In the cohort of NSCLC patients treated between 1990 and 2000, squamous cell carcinoma (SCC) histology and pre-treatment anemia (Hgb <110 g/L), leukocytosis (WBC > 9.0 x109/L), and thrombocytosis (Plt >350 x109/L) were independent prognostic factors for shorter overall survival. However, in the chemoradiation cohort only thrombocytosis retained independent prognostic significance in a multivariate analysis. In the cohort of patients with recurrent disease treated with palliative systemic therapy, only leukocytosis was significantly associated with worse survival. Conclusions: Routine pre-treatment hematopoietic blood parameters—together with other prognostic factors such as disease stage and performance status—can provide decision-making support when individualizing treatment of NSCLC. The prognostic role of histology is unclear and further research is warranted to determine its significance.
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PASSIGLIA, Francesco. "Immune-Biomarkers in Advanced Non-Small Cell Lung Cancer." Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/514194.
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N.ABackground: Developing personalized immunotherapy-based approaches, through the identification of predictive immune-related biomarkers, is still a main topic for translational lung cancer research. In the present study we investigated whether baseline tissue “immune-related gene signatures”, as well as plasma chemo-cytokines profiles, could predict sensitivity/resistance to immune-checkpoint inhibitors in pre-treated patients with advanced non-small cell lung cancer (NSCLC). Methods: From September 2015 to September 2018, 150 patients with previously treated advanced NSCLC who received either anti-PD1 or anti-PD-L1 inhibitors in the second-third line setting were included within this translational study. All the patients underwent CT-scan every 6 cycles and responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Gene expression analysis was performed on 86 FFPE tissue samples by using the nCounter® PanCancer IO360™ Panel applied on NanoString platform, in order to analyze 770 genes involved in key immuno-oncology pathways. Peripheral blood samples were obtained from 57 patients at baseline and 37 patients at the 6th week under IO-therapy. A panel of cytokines and chemokines (IL-6, IL-8, CXCL10, CX3CL1, CCL2, VEGF, and IFN- gamma) were quantified in plasma by Cytokine Bead Array and their association with OS and TTP was assessed by Adaptive Index Modeling multivariable analysis. NLR and PLR were also assessed for potential association with clinical outcomes. Results: The gene expression levels of IL12RB2, ESR1 and CCL8 (p-values = 0.000308, 0.00162 and 0.0398, respectively) resulted significantly higher in responders versus non-responders patients. In patients with 0S > 18 months, a significant upregulation of the ESR1 (p-value = 0.00813) and IL12RB2 (p-value = 2.48e-08) genes, as well as a higher score for lymphoid compartment (p-value = 0.0117), cytokine and chemokine signaling (p-value = 0.0268), costimulatory signaling (p-value = 0.0323), and cytotoxicity (p-value = 0.0412), was observed. As regards peripheral blood samples analysis, an Immune-suppressive blood index score (ISBIS) was identified clustering patients into 3 groups with progressively worsening TTP and OS. The score was composed by higher IL-8 and CCL-2 levels, higher NLR, and lower IFN-gamma level. The differences among both PFS and OS Kaplan Meyers curves across the different subgroups were statistically significant (p < 0.0001). Conclusion: These data suggest that the systemic balance between neutrophil-related inflammation and lymphocyte anti-tumor immunity may condition response to immunotherapy in lung cancer, with clinical benefit primarily occurring in patients with such a preexisting, intra-tumoral T-cell adaptive immune response. Correlative tissue immune gene signatures as well as circulating cyto-chemokine emerged as potential indicators of a T cell– inflamed phenotype necessary for the clinical activity of PD-1/PD-L1 inhibitors.
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Wong, Kit-man Sunny, and 王傑民. "Isolation and characterization of cancer stem cells in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47250665.
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Tumor heterogeneity has long been observed and recognized as a challenge to
cancer therapy. The cancer stem cell (CSC) model is one of the hypotheses
proposed to explain such a phenomenon. A specific cancer stem cell marker has
not been determined for non-small cell lung cancers (NSCLC), preventing the
definitive evaluation of whether the biology of NSCLC is governed by the CSC
model. This study aimed to analyze the expression of candidate CSC markers and
using the identified putative marker, to isolate CSC and determine the
applicability of the CSC model in NSCLC.
The expression or activities of four putative stem cell markers, CD24, CD44,
CD133 and aldehyde dehydrogenase 1 (ALDH1) were measured by flow
cytometry in eight NSCLC cell lines before and after chemotherapy for 24 hours.
Markers with increased expression after treatment were considered potential CSC
markers and used for isolating tumor cell subpopulations from the untreated cell
lines by fluorescence-activated cell sorting (FACS). Confirmatory analyses using
widely acceptable methodology were performed to test for CSC properties in the marker+ and marker- subpopulations. Isolated subpopulations were further
characterized by functional and phenotypic studies.
Flow cytometry showed amongst the 4 markers, only ALDH1 expression was
significantly enhanced by chemotherapeutic treatment, suggesting ALDH1 could
be a CSC marker. Untreated ALDH1+ cells formed significantly more and larger
cell spheres in non-adherent, serum-free conditions than ALDH1- cells. Likewise,
higher in vitro tumorigenic ability was observed in ALDH1+ subset using colony
formation assay. Furthermore, a higher resistance to cytotoxic drugs was observed
in ALDH1+ compared to ALDH1- cells. In vivo studies also showed ALDH1+ cells
showed higher tumorigenicity than ALDH1- cells; as few as 2,500 ALDH1+ cells
formed tumor in SCID mice which were serially transplantable to 2nd and 3rd
recipients, while no tumor was formed from ALDH- cells with even ten times the
number of cells. Also, expression analysis revealed higher expression of the
pluripotency genes, OCT4, NANOG, BMI1 and SOX9, in ALDH1+ cells. In view
of previous studies reporting CD44 as a CSC marker in lung cancer, double
marker selection of putative CSC was performed to compare ALDH1+CD44+ and
ALDH1-CD44+ subpopulations. Results of the spheroid body formation assay and
cisplatin treatment experiments revealed the ALDH1+CD44+ subpopulation
possessed higher self-renewal ability and chemo-resistance. Cell migration and
invasion assays showed differences between the ALDH1+CD44+ and ALDH1-
CD44+ subpopulations. The significance of these observations require further
investigation.
In conclusion, the result showed that ALDH1 could be a marker for NSCLC stem
cells as evidenced by enhanced self-renewal and differentiation abilities in
ALDH1+ subpopulation. Furthermore, this study observed the presence of at least
two potential stem cell subpopulations in NSCLC cells with differential selfrenewal,
chemotherapy resistance and cell mobility properties. Further
investigations are required to validate these observations and to investigate the
underlying mechanisms. Better understanding of these issues would help to solve
the challenges brought by tumor heterogeneity in lung cancer therapy.published_or_final_version
Pathology
Master
Master of Philosophy
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陳潔盈 and Kit-ying Loucia Chan. "Expression analysis of Candidate cancer genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011163.
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Sarvi, Sana. "Small cell lung cancer and cancer stem cell-like cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9542.
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Small cell lung cancer (SCLC) is a highly aggressive malignancy with extreme mortality and morbidity. Although initially chemo- and radio-sensitive, almost inevitable recurrence and resistance occurs. SCLC patients often present with metastases, making surgery not feasible. Current therapies, rationally designed on underlying pathogenesis, produce in vitro results, however, these have failed to translate into satisfactory clinical outcomes. Recently, research into cancer stem cells (CSCs) has gained momentum and form an attractive target for novel therapies. Based on this concept, CSCs are the cause of neoplastic tissue development that are inherently resistant to chemotherapy, explaining why conventional therapies can shrink the tumour but are unable to eliminate the tumour completely, leading to eventual recurrence. Here I demonstrate that SCLC H345 and H69 cell lines contain a subset of cells expressing CD133, a known CSC marker. CD133+ SCLC sub-population maintained their stem cell-like phenotype over a prolonged period of culture, differentiated in appropriate conditions and expressed the embryonic stem cell marker Oct-4 indicating their stem-like phenotype. Additionally, these cells displayed augmented clonogenic efficacy, were chemoresistant and tumorigenic in vivo, distinct from the CD133- cells. Thus, the SCLC CD133 expressing cells fulfil most criteria of CSClike definition. The molecular mechanisms associated with CD133+ SCLC chemoresistance and growth is unknown. Up-regulated Akt activity, a known promoter of resistance with survival advantage, was observed in CD133+ SCLC cells. Likewise, these cells demonstrated elevated expression of Bcl-2, an anti-apoptotic protein compared to their negative counterpart explaining CD133+ cell chemoresistance phenotype. Additionally, CD133+ cells revealed greater expression of neuropeptide receptors, gastrin releasing peptide (GRP) and V1A receptors compared to the CD133- cells. Addition of exogenous GRP and arginine vasopressin (AVP) to CD133+ SCLC cells promoted their clonogenic growth in semi-solid medium, illustrating for the first time neuropeptide dependent growth of these cells. A novel peptide (peptide-1) was designed based on the known structure of the substance P analogues that have shown benefit in animal models and in early clinical trials. This compound inhibited the growth of SCLC cells in in vitro with improved potency and stability compared to previous analogues and reduced tumorigenicity in vivo. Interestingly, peptide-1 was more effective in CD133+ cells due to increased expression of neuropeptide receptors on these cells. In conclusion, my results show that SCLC cells retain a sub-population of cells that demonstrate CSC-like phenotype. Preferential activation of Akt and Bcl-2 survival pathways and enhanced expression of neuropeptide receptors contribute to CD133+ SCLC chemoresistance and growth. Therefore, it can be proposed that CD133+ cells are the possible cause of SCLC development, treatment resistance and disease recurrence. Despite being chemoresistant, CD133+ cells demonstrated sensitivity to peptide-1. The identification of such new analogue that demonstrates efficacy towards resistant CD133+ SCLC cells is a very exciting step forward in the identification of a potential new therapy for resistant disease.
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Chan, Kit-ying Loucia. "Expression analysis of Candidate cancer genes in non-small cell lung cancer /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38480360.
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譚郭雅欣 and Gloria Tam. "Non-small cell lung cancer clinical trials on new medicines." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41711956.
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Tai, Lai-shan. "Molecular genetic characterizations of human non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31375315.
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Casadevall, Aguilar David. "Heterogeneity of biomarker expression in non-small cell lung cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457975.
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L’èxit de de la medicina de precisió en oncologia depèn, en gran mesura, d’una adequada selecció dels pacients que rebran teràpies dirigides contra dianes específiques del seu tumor. Per poder seleccionar els pacients, és indispensable disposar de biomarcadors amb valor predictiu que informin les decisions terapèutiques.
MET i PD-L1 són dos receptors de membrana rellevants en la biologia del carcinoma pulmonar no microcític (CPNM). MET és un oncogen i l’activació de la seva via es troba relacionada amb múltiples processos pro-tumorals com són la proliferació i la motilitat cel·lulars, així com la invasió d’estructures veïnes. PD-L1 és una molècula clau en la resposta immunitàries, i la seva sobre-expressió en els tumors està relacionada amb la capacitat de les cèl·lules tumorals d’evitar el seu reconeixement i destrucció per part del sistema immunitari. Actualment, existeixen teràpies específiques dirigides contra aquestes molècules. L’estratègia més emprada per seleccionar els pacients que se’n poden beneficiar és la determinació de l’expressió d’ambdues molècules en teixit tumoral. Tanmateix, el valor de MET i de PD-L1 com a biomarcadors predictius i el mètode pel qual s’han de determinar és subjecte de debat.
Estudis recents han detectat un alt grau d’heterogeneïtat genòmica en mostres tumorals en CPNM. Aquesta heterogeneïtat podria afectar de forma rellevant la classificació de pacients basada en l’expressió de biomarcadors. A més, aquest fet seria especialment rellevant en el cas del CPNM, ja que l’estudi de biomarcadors es fa generalment en mostres petites de teixit, provinents de biòpsies o citologies obtingudes mitjançant tècniques mínimament invasives. L’objectiu principal dels treballs presentats en aquesta tesi és estudiar l’heterogeneïtat de l’expressió de MET i PD-L1 en mostres de CPNM.
Amb aquesta finalitat, hem analitzat mostres tumorals procedents de pacients tractats quirúrgicament de CPNM a l’Hospital del Mar. De cada tumor, hem seleccionat múltiples àrees geogràficament separades, les quals hem analitzat de forma independent. En l’estudi en que hem avaluat MET hem seleccionat quatre àrees per cada pacient, mentre que en l’estudi de PD-L1 n’hem seleccionat dues. En cada àrea tumoral, hem mesurat l’expressió de MET i de PD-L1 mitjançant mètodes d’immunohistoquímica i d’hibridació in situ fluorescent (FISH). Finalment, hem comparat l’expressió de MET i de PD-L1 entre diferents àrees tumorals.
En el cas de MET, hem trobat discordances entre diferents àrees tumorals en un 20-40% per immunohistoquímica i en un 25-50% per FISH. En el cas de PD-L1, aquesta discordança ha estat major si es valora només l’expressió en limfòcits infiltrants de tumor (17-27%) que si es valora en cèl·lules tumorals (10-19%). A més, un 36% dels casos amb amplificació del gen que codifica PD-L1 determinada per FISH presenten aquesta amplificació només en una de les dues àrees analitzades.
En conjunt, els nostres resultats suggereixen que l’expressió d’ambdós biomarcadors és heterogènia, tant si es mesura mitjançant immunohistoqumímica com mitjançant FISH. Aquesta heterogeneïtat pot tenir un impacte potencial en la classificació de tumors basada en l’expressió de biomarcadors i per tant, pot suposar una dificultat afegida a l’hora de desenvolupar teràpies dirigides per pacients amb CPNM.The success of precision medicine in oncology is dependent to a large extent on an adequate selection of patients who will receive targeted therapies aimed at specific molecular traits of their tumor. In order to be able conduct such patient selection, predictive biomarkers that can inform therapeutic decisions are essential. MET and PD-L1 are two relevant membrane receptors for non-small cell lung cancer (NSCLC) biology. MET is an oncogene the activation of which is involved in multiple pro-tumorigenic processes such as cell proliferation, motility and invasion. PD-L1 is a key molecule that acts during the immune response, and its overexpression in tumors is thought to mediate the ability of tumor cells to avoid immune cell recognition and destruction. Currently, there are specific therapies directed against these molecules. The most commonly used strategy to select the patients that will benefit from such drugs is the analysis of the expression of both molecules in tumor tissue. However, the value of MET and PD-L1 as predictive biomarkers and the method by which it should be determined is a subject of debate. Recent studies have detected a high degree of genomic heterogeneity in NSCLC tumor samples. This heterogeneity could significantly affect biomarker-based patient classification especially in the case of NSCLC, since biomarker studies are usually performed in small biopsies or cytology samples obtained through minimally invasive techniques. The main objective of the work presented in this thesis is to study the heterogeneity of the expression of MET and PD-L1 in NSCLC samples. For this purpose, we have analyzed tumor samples from NSCLC patients that had undergone surgical treatment at Hospital del Mar. Of each tumor, we have selected multiple geographically separate areas, which we analyzed independently. In the study evaluating MET, we selected four tumor areas per patient, while in the study evaluating PD-L1 we selected two areas. In each tumor area, we measured the expression MET and PD-L1 using immunohistochemical and fluorescence in situ hybridization methods (FISH). Finally, we compared the expression of MET and PD-L1 in different tumor areas. Regarding MET, we have found discordances between different tumor areas in 20-40% of cases using immunohistochemistry and in 25-50% of cases using FISH. Regarding PD-L1, this discrepancy was greater if we evaluated PD-L1 expression in tumor infiltrating lymphocytes (17-27%) than if we did so only in tumor cells (10-19%). Moreover, 36% of the cases with amplification of the gene coding for PD-L1 determined by FISH presented gene amplification only in one of the two areas analyzed. Overall, our results suggest that the expression of both biomarkers is heterogeneous, whether measured by immunohistochemistry or by FISH. This heterogeneity can have a potential impact on the classification of tumors based on the expression of biomarkers and, therefore, could represent a hurdle for the development of targeted therapies for NSCLC patients.
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Tong, Wing-yee. "Studies on non-small cell lung cancer with EGFR mutation /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31495333.
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Cox, Giles. "Angiogenesis and matrix metalloproteinases in non-small cell lung cancer." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29608.
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The aim of this study was to evaluate potential invasive and metastatic pathways in order to develop a biological prognostic model for operable NSCLC. Initially an immunohistochemical study of angiogenesis, growth factor receptors (EGFR, c-erbB-2), regulators of apoptosis (p53, Bcl-2) and matrix metalloproteinases and their inhibitors (MMP-2, MMP-9 and TIMP-2) was performed in a retrospective series of resected NSCLC tumours. Chalkley counting of CD34-immunostained microvessels was used as an indirect measure of angiogenesis. A high Chalkley count was an independent marker of poor outcome. Bcl-2 expression correlated with good prognosis suggesting that loss of Bcl-2 expression may indicate more severe molecular dedifferentiation resulting in a more aggressive phenotype. MMP-2, MMP-9 and TIMP-2 were frequently demonstrated in both tumour cells and the surrounding stroma. Tumour cell MMP-9 expression was independently associated with poor prognosis and significantly correlated with EGFR immunoreactivity. A stage-independent prognostic model using the immunohistochemical markers CD34, EGFR, MMP-9 and Bcl-2 performed on routinely processed tissue was developed. This model identified patients at particular risk of recurrence after resection who could receive adjuvant treatment with either traditional cytotoxic chemotherapy or potentially individualised therapy with more targeted therapeutic agents. In vitro studies demonstrated that EGF up-regulated MMP-9 mRNA expression in 4/5NSCLC cell-lines with no effect on MMP-2, MTI-MMP, TIMP-1 or TIMP-2 mRNA expression. These results suggest EGFR is involved in the specific up-regulation of MMP-9 and supports the use of novel therapies including MMP inhibitors and EGFR tyrosine kinase antagonists in the treatment of NSCLC.
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Tai, Lai-shan, and 戴麗珊. "Molecular genetic characterizations of human non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31375315.
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Tong, Wing-yee, and 唐穎儀. "Studies on non-small cell lung cancer with EGFR mutation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45010432.
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Koch, Andrea. "Clinical Aspects of Inflammation in Non-small Cell Lung Cancer." Doctoral thesis, Linköpings universitet, Internmedicin, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-68749.
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Lung cancer is the most common cause of cancer death worldwide, with about 1.2 million deaths every year. In Sweden, about 3500 new cases are diagnosed every year. The majority of patients presents with advanced non-small cell lung cancer (NSCLC) and is treated with palliative intent. Standard treatment in these patients in performance status 0-2 is combination chemotherapy. Radiotherapy may be added for palliative purposes. Median survival time with such treatment is 6-10 months. New treatment strategies are urgently needed. There is growing evidence for a link between cancer and inflammation and consequently, inflammation may be a possible target for the treatment of lung cancer. The aim of this thesis was to study clinical aspects of inflammation in non-small cell lung cancer. A central issue was to adapt the projects as close to clinical routine as possible. In a retrospective study of 289 patients (paper I), we investigated the prognostic value of Creactive protein (CRP), a nonspecific marker of systemic inflammation, and smoking in patients with advanced NSCLC treated with palliative first-line chemotherapy. We found that patients with elevated CRP values (≥10 mg/ml) and current smokers at onset of treatment had inferior survival compared to patients with normal CRP values and patients who were not smoking. CRP and smoking status were independent prognostic factors and provided additional information to established prognostic factors such as stage of disease and performance status. The expression of COX-2, an important enzyme involved in inflammation, was prospectively analysed in 53 patients with cytologically diagnosed lung cancer (paper II). The study showed that the analysis of COX-2 expression in cytological material is technically easy to perform with routine diagnostic methods and results in good quality slides. There was great variation in the proportion of COX-2 positive cells between the patients as well as in the intensity of staining between individual cells in many single cases. The major project (paper III) of this thesis was the CYCLUS study, an academic, randomised, double-blind, phase III trial. The scientific question was if addition of the COX-2 inhibitor celecoxib to first-line palliative chemotherapy would prolong survival in patients with advanced NSCLC. 316 patients were included at 13 centres in Sweden. There was no survival difference between the treatment arms. Celecoxib appeared to have more favourable effect on survival in women than in men, but the differences were not significant. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.
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Kouverianou, Eleni. "Galectin-3 regulation of non small cell lung cancer growth." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17891.
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Galectin-3 is a β-galactoside binding lectin expressed in tumour cells and macrophages and has been associated with increased malignancy in a variety of cancers. Previous work has shown that galectin-3 is an important regulator of macrophage function, promoting an alternative (M2) phenotype which potentiates chronic inflammation and fibrosis. Tumour associated macrophages (TAMs) adopt an M2 phenotype and are thought to promote tumour growth by down regulating T cell effector function and promoting angiogenesis. This project examines the hypothesis that host galectin-3 promotes lung cancer growth and spread. In order to test this hypothesis, Lewis Lung Carcinoma tumour growth and metastasis was investigated in strain matched mice either expressing or deficient in galectin-3. The Lewis Lung Carcinoma cell line (LLC1) is a spontaneous lung carcinoma line, derived from C57BL/6 mice, which readily forms tumours when transplanted. Furthermore, LLC1 cells were stably transfected with a Luciferase expressing vector in order to assist detection of tumour growth and metastasis in vivo. An orthotopic model of LLC1 growth suggested that galectin-3-/- animals do not support lung carcinoma growth and spread. This finding was confirmed by a subcutaneous model of cancer growth, where it was found that wild type animals display a higher proportion of macrophages expressing a prototypic M2 marker around tumour sites compared to galectin-3-/- animals. M2-promoting cytokine transcripts were also reduced in galectin-3-/- mice. Additionally, tumours of wild type mice were more invasive and presented more mature blood vessels compared to galectin-3-/- mice. To specifically address the role of recruited cells on tumour growth, metastasis and the inflammation profile around tumour sites, in relation to galectin-3 expression, bone marrow cells (BMCs) were transplanted from wild type to galectin-3-/- mice and vice versa. It was shown that galectin-3 positive BMCs restore the wild type phenotype of tumour growth in galectin-3-/- mice, while galectin-3 deficient BMCs impair tumour growth in wild type animals. Furthermore, macrophage ablation experiments demonstrated incapacity for tumour establishment in the absence of macrophages. A series of experiments investigating reported inhibition of galectin-3 by modified citrus pectin (MCP) via competitive inhibition did not provide conclusive results. MCP had no effect in vivo, but was able to inhibit LLC1 cell growth in vitro. Most importantly though, results were inconclusive as to whether galectin-3 binds MCP. Some ligand displacement was seen, but direct binding of the molecules could not be shown. In general, the results obtained demonstrate a strong pro-tumoural effect of galectin-3 on growth, tissue invasion and metastasis of LLC1 tumours via an increased proportion of Ym1-expressing macrophages around tumour sites. It was shown that macrophages are key cells for tumour initiation and that BMC phenotype in relation to galectin-3 expression determines the phenotype of tumour development in subcutaneous and orthotopic LLC1 models. Therefore, galectin-3 has a strong regulatory effect on tumour phenotype and could present a key target in the management of lung carcinomas.
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Usó, Marco Marta. "ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER." Doctoral thesis, Universitat Politècnica de València, 2015. http://hdl.handle.net/10251/51283.
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[EN] Lung cancer is the leading cause of cancer-related death worldwide, and is the third most common cancer type; it can be classified into two subgroups based on histology: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The 5-year survival still remains poor and despite the existence of several distinct tumour phenotypes, therapeutic decisions are mainly based on clinical features such as stage or performance status. This highlights the need for new diagnostic and prognostic biomarkers in different types of samples (such as blood, fresh-frozen tissue or formalin-fixed, paraffin-embedded samples).
The field of tumour immunology has changed in the last decade, and it is now accepted that the immune system plays a pivotal role in cancer. Although the immune cells that infiltrate the tumour microenvironment are potentially capable of eliminating tumour cells, they cannot prevent tumour development and progression. Tumours acquire mechanisms to regulate their immune microenvironment such as the release of a series of factors to subvert normal reaction mechanisms, the modulation of co-stimulatory pathways, also known as immune checkpoints, and the induction and attraction of suppressor cells (myeloid-derived suppressor cells, tumour-associated macrophages, and regulatory T cells). The potential effect of the patient's immune system on clinical outcome is important for the identification of prognostic markers as well as markers that predict treatment responses. The study of immune-related markers, especially those implicated in immunoregulatory processes, could provide valuable prognostic information that could help in many applications in future clinical practice.
Thus, the objective of this thesis is to characterise cancer immunoregulation biomarkers and to evaluate the possible correlation between these biomarkers and clinicopathological and prognostic variables in patients with NSCLC by the use of well-tested and accurate techniques such as quantitative PCR and immunohistochemistry. Furthermore, this study will provide information about the immunological features of the tumour microenvironment in NSCLCs.[ES] El cáncer de pulmón es una de las principales causas de muerte relacionada con cáncer en el mundo, siendo el tercer tipo de cáncer más común. El cáncer de pulmón no microcítico (CPNM) representa casi el 85% de todos los cánceres de pulmón y la supervivencia a los 5 años va desde el 50% en estadios IA hasta el 15% en estadios IIIA. Hasta el momento, no se han descubierto biomarcadores capaces de predecir la progresión de la enfermedad en pacientes tanto en estadios resecables como en estadios avanzados, por lo que existe una clara necesidad de realizar estudios centrados en la búsqueda de biomarcadores pronósticos y diagnósticos en los diferentes tipos de muestra disponibles, como por ejemplo sangre, tejido fresco y tejido parafinado. El campo de la inmunología tumoral ha cambiado en la última década y actualmente se sabe que el sistema inmune juega un papel clave en cáncer. Las células inmunes que infiltran el tumor son un componente más del microambiente tumoral. Pese a que son potencialmente capaces de eliminar los antígenos tumorales, estas células no pueden evitar la formación y progresión tumoral. Esto es debido a que el tumor adquiere diversos mecanismos de regulación del microambiente tumoral con el objetivo de escapar del ataque del sistema inmune, como por ejemplo liberación de factores que impiden el correcto funcionamiento de los mecanismos de reacción inmune, modulación de vías co-estimuladoras y reclutamiento y activación de células inmunoreguladoras como las células T reguladoras, las células mieloides supresoras y los macrófagos asociados a tumores. El estudio de marcadores relacionados con la respuesta inmune y concretamente con los procesos de inmunoregulación puede proporcionarnos información pronóstica y predictiva relevante sobre los pacientes con cáncer. Por todo ello, el principal objetivo de esta tesis doctoral es analizar la presencia de marcadores relacionados con la inmunoregulación y evaluar su posible correlación con las variables clínico-patológicas y pronósticas en pacientes con CPNM mediante el uso de técnicas fiables y aplicables en la práctica clínica como la PCR cuantitativa y la inmunohistoquímica. Así mismo, esto nos permitirá conocer en mayor profundidad las características inmunológicas del microambiente tumoral en pacientes con CPNM.
[CAT] El càncer de pulmó és una de les principals causes de mort relacionades amb càncer al món, sent a més a més el tercer tipus de càncer més comú. El càncer de pulmó no microcític (CPNM) representa el 85% de tots els casos de càncer de pulmó aproximadament i la supervivència als 5 anys continua sent molt baixa. Fins el moment, no s'han descobert biomarcadors capaços de predir la progressió de la malaltia tant en pacients en estadis inicials com en estadis avançats. Per aquest motiu, existeix una clara necessitat de realitzar estudis centrats en la recerca de biomarcadors pronòstics i predictius en els diferents tipus de mostres disponibles, com per exemple sang, teixit fresc i teixit parafinat. El camp de la immunologia tumoural ha canviat en l'última dècada i actualment se sap que el sistema immune exerceix un paper clau en el càncer. Les cèl¿lules immunològiques que infiltren el tumour són un component més del microambient tumoural. Malgrat que aquestes cèl¿lules són potencialment capaces d'eliminar el antígens tumourals, s'ha evidenciat que no poden previndre la formació i progressió tumoural. Una de les raons per les quals s'observa aquest fenomen és que el tumour adquireix diversos mecanismes de regulació del microambient tumoural. Aquests mecanismes es basen en l'alliberació de factors que impedeixen el correcte funcionament del sistema immune, la modulació de vies coestimuladores i el reclutament i activació de cèl¿lules immunoreguladores com poden ser les cèl¿lules T reguladores, les cèl¿lules mieloides supressores i els macròfags associats a tumour. L'estudi de marcadors relacionats amb la resposta immune i més concretament amb els processos d' immunoregulació pot proporcionar informació pronòstica i predictiva rellevant sobre els pacients amb càncer. Per tot això, el principal objectiu d'aquesta tesi doctoral és analitzar la presència de marcadors relacionats amb la immunoregulació i avaluar la seva possible correlació amb les variables clinicopatològiques i pronòstiques de pacients amb CPNM mitjançant l'ús de tècniques fiables i aplicables a la pràctica clínica com són la PCR quantitativa i la immunohistoquímica. Així mateix, aquestes anàlisis ens permetran conèixer amb major profunditat les característiques immunològiques del microambient tumoural de pacients amb CPNM.
Usó Marco, M. (2015). ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/51283
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Deskin, Brian J. "Histone deacetylase 6 functions in non-small cell lung cancer." Thesis, Tulane University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10195328.
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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide in both men and women. Of relevance to our research presented herein are the Transforming growth factor β (TGF-β) signaling pathways and the heat shock response in the context of NSCLC. Dysregulation of TGF-β signaling often results in disease and is a common feature of many cancers including NSCLC where it governs cell fate and epithelial plasticity through the epithelial-to-mesenchymal transition (EMT). Another key feature of oncogenic TGF-β signaling is the crosstalk with other oncogenic pathways, like the NOTCH signaling pathway, which aids to restrict differentiation and modulates proliferation. Our research identified a mechanistic link between histone deacetylase 6 (HDAC6) and TGF-β1-induced Notch1 signaling. When HDAC6 is knocked down with siRNA or its deacetylase function is pharmacologically inhibited TGF-β1 activation of Notch signaling is abrogated. Within this paradigm we identified a protein complex consisting of HDAC6, heat shock protein 90 (HSP90), and the Notch1 receptor. In response to TGF-β1 stimulation, HDAC6 rapidly deacetylates HSP90 at lysine 294 which corresponds with cleavage and activation of Notch1.
Our investigations also uncovered a unique feature of HSP90 function in NSCLC. Activation of the heat shock response triggers activation of Notch1 signaling. We demonstrated that HDAC6 regulates this heat shock-induced Notch1 signaling through modulation of HSP90 function of cytoplasmic sequestration of the key transcription factor that governs the heat shock response, heat shock factor 1 (HSF1). Brief exposure of NSCLC cells to 42°C activates heat shock-induced Notch1 signaling, knockdown of HDAC6 with siRNA or pharmacological inhibition of HDAC6 abrogated this induction. In our investigations employing this combined strategy of targeting both HDAC6 and HSP90 we discovered that this treatment had an additive effect to enhance apoptotic markers and inhibit cell cycle progression in NSCLC cells. Individual HDAC6 or HSP90 inhibition slowed tumorigenesis and enhanced apoptosis of NSCLC in vivo. Taken altogether, our research identifies HDAC6 and HSP90 as regulators of key oncogenic pathways required for EMT and that combined inhibition of both these targets is a rational strategy to selectively kill NSCLC cells.
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Tam, Gloria. "Non-small cell lung cancer clinical trials on new medicines." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41711956.
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Fujimoto, Masakazu. "Stromal plasma cells expressing immunoglobulin G4 subclass in non-small cell lung cancer." Kyoto University, 2015. http://hdl.handle.net/2433/199170.
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柳言樺 and Yin-wah Lau. "Mutation and expression analysis of PTEN in non-small cell lung cancerfrom non-smokers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41650931.
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Li, Tung-ching Kathy. "Hypermethylation of tumor suppressor genes in non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2003. http://sunzi.lib.hku.hk/hkuto/record/B31971180.
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Pikor, Larissa A. "Molecular mechanisms underlying tumorigenesis of non-small cell lung cancer subtypes." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/48492.
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Lung cancer is the leading cause of cancer death in Canada and worldwide. A late stage of diagnosis in conjunction with a lack of effective treatment options are largely responsible for the poor survival rates of lung cancer. Histological subtypes of lung cancer are known to respond differently to standard therapies, suggesting they are distinct diseases. A better understanding of the molecular alterations and underlying biology of lung cancer subtypes is therefore necessary for the development of novel detection and treatment strategies in order to improve patient prognosis. We hypothesize that lung adenocarcinoma (AC) and squamous cell carcinoma (SqCC) arise through disparate patterns of molecular alterations and that these differences underlie unique biological mechanisms that contribute to subtype development, phenotypes and response to therapy.
In this thesis, I apply multidimensional integrative 'omics approaches to characterize the genomic and epigenomic landscapes of AC and SqCC and elucidate differential patterns of alterations and subtype specific gene disruptions causal to NSCLC and the development of specific subtypes. The integration of DNA copy number, methylation, gene and miRNA expression data on AC and SqCC tumors and patient matched non-malignant tissue identified several subtype specific alterations and revealed unique oncogenic pathways associated with AC and SqCC that can be successfully targeted by existing therapies. By combining genomic analyses with manipulation of candidate genes in vitro and in vivo, we validated the contribution of candidate genes to tumorigenesis and determined the mechanisms through which they contribute to disease pathogenesis. In addition to revealing differentially disrupted genes and pathways we also identified numerous alterations common to both subtypes.
Collectively, this work has further characterized the landscape of molecular alterations that define AC and SqCC, and the mechanisms through which these alterations contribute to subtype tumorigenesis. This work has identified novel candidate genes involved in subtype tumorigenesis as well as miRNAs with potential as diagnostic biomarkers for lung cancer. Taken together, these findings underscore the importance of tailoring treatment strategies to the histological subtype based on the underlying biology of that subtype.Medicine, Faculty of
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Leung, Ada Wai Yin. "Improving platinum-based treatments for advanced non-small cell lung cancer." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58850.
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Novel treatments are urgently needed for patients with non-small cell lung cancer (NSCLC). Currently, these patients are almost always first treated with cisplatin (CDDP)-containing drug combinations. To identify therapeutic targets that could enhance CDDP activity, a genome-wide siRNA screen looking for synthetic lethal partners with low-dose CDDP was completed. These data were combined with results from a microarray study assessing differentially expressed genes in NSCLC cells exposed to low-dose CDDP. The results indicated that 151 genes were differentially expressed in cells exposed to low-dose CDDP. Nine up-regulated genes ranked within the top 10% of the siRNA screen based on a scoring method that considered minimal loss of cell viability from gene knockdown alone and significant enhancement of CDDP activity. Five genes were further validated and two (RRM2B and CABYR) were found to significantly improve the cytotoxic effects of CDDP. Pathways involved in repairing double-stranded DNA breaks and INO80 chromatin remodeling were enriched in both datasets. Analysis of the kinome subset of the siRNA screen also identified PAPSS1 (3’-phosphoadenosine 5’-phosphosulfate synthase 1) as a protein that when silenced sensitized NSCLC cells to CDDP. PAPSS1 produces the biologically active form of sulfate for sulfonation reactions. PAPSS1-silencing combined with low-dose CDDP reduced the clonogenicity of NSCLC cells by 98.7%, increased DNA damage, and induced G1/S phase cell cycle arrest. PAPSS1 suppression also sensitized NSCLC cells to radiation and topoisomerase I inhibitors. Sensitization was cancer cell specific. The extent of CDDP potentiation increased substantially when NSCLC cells were stressed by starvation or hypoxia. In NSCLC cell spheroids and zebrafish xenografts, PAPSS1 silencing in combination with CDDP decreased tumor size, while the same dose of CDDP combined with non-silencing controls led to increases in tumor size. In a subcutaneous tumour model, expression of PAPSS1-targeting shRNA in combination with a non-curative dose of CDDP enhanced activity compared to controls. Future studies are needed to identify small molecule inhibitors and proteins that interact with PAPSS1. These tools will be useful to fully understand the mechanisms by which chemosensitization occurs and such tool compounds may prove useful as therapeutics that would benefit NSCLC patients when first treated.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
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Wilson, Ian Michael. "Concerted genomic and epigenomic alterations in non-small cell lung cancer." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/26490.
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Background: Around the world, lung cancer is the leading cause of cancer-related death and a major public health problem. A diagnosis of lung cancer carries a remarkably poor prognosis, even after years of research into the disease. The advent and availability of tools to survey the genomes and epigenomes of lung cancers is beginning to yield real clues into the molecular nature of the disease. These clues are being turned into new diagnostic and therapeutic tools with increasing regularity. We used modern high-resolution and high-throughput tools to identify novel genes implicated in various lung cancer phenotypes and aspects of lung cancer pathogenesis.
Hypotheses: (1) Combined profiling of lung cancer genomes and epigenomes will identify critical lung cancer genes that are simultaneously affected by DNA copy number and DNA methylation aberrations. (2) The susceptibility locus on chromosome 6q, identified through familial linkage studies, contains an unidentified tumor suppressor gene (3) Key genes involved in lung cancer phenotypes can be identified through the elucidation of discriminating genomic and epigenomic alterations.
Materials/Methods: Genomic and epigenomic data were analyzed independently and pair-wise to identify genes in NSCLC whose alterations are associated with NSCLC risk, development and phenotype. These genomic and epigenomic data were used in conjunction with a multitude of mRNA and protein-level assays to further refine candidate lists and validate their disruption. Targeted molecular silencing of a candidate TSG was used in conjunction with cellular assays to investigate and confirm the role of this gene in NSCLC.
Results: We designed and optimized an experimental/analysis framework for the combined interrogation of epigenomic and genomic data. We used this framework to identify a novel lung cancer tumor suppressor gene, EYA4, that is frequently disrupted in lung cancers, and is associated with NSCLC risk. Following this, we identified subtype-specific genomic and epigenomic alterations with consequent gene expression changes in NSCLC subtypes. Lastly, we identified specific phenotypic characteristics of the subtypes affected by the DNA alterations.
Conclusions: Integrated analysis of the genomes and epigenomes of NSCLC tumors provides a unique approach for the discovery of key cancer-related genes.
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李冬靑 and Tung-ching Kathy Li. "Hypermethylation of tumor suppressor genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31971180.
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Liao, Rachel Grace. "Functional Studies of Candidate Oncogenes in Non-Small Cell Lung Cancer." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11173.
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Cancer is a set of complex genetic diseases driven by diverse genomic alterations. The genomic study of cancer has enabled the discovery of novel, targetable events in almost all cancer types and in turn, has led to the development of new, targeted cancer therapies benefiting patients; however, the recent explosion of genomic datasets has also resulted in huge lists of new oncogenic factors of unknown biological relevance, and uncertainty over how best to use the data appropriately to influence patient care. Some of the most pressing questions surround the use of statistical methods to identify actionable genomic alterations in cancer and the identification of driving oncogenes in the context of the genomic evolution of cancer cells, undergone before, during, and after prolonged treatment regimens.
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Arikatla, Swetha. "Effect of Tumor Microenvironmental Conditions on Non Small Cell Lung Cancer." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/126.
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Tumor microenvironmental conditions play a vital role in promoting metastasis and tumor recurrence. Due to inefficient vasculature, cancer cells experience hypoxia, glucose deprivation and low pH even during the early stages of tumor growth. Tumor cells are proposed to adapt to these microenvironmental conditions by acquiring increased migratory and invasion potential and tumor initiating ability. Our research addresses the effect of these biochemical factors of the tumor microenvironment (TME) on motility, epithelial to mesenchymal transition (EMT) and stemness of non-small cell lung cancer (NSCLC). NCI-H292 and NCI-H1650 NSCLC cell lines were used to measure the effect of the above mentioned TME conditions. Apart from acidic pH, low glucose and hypoxia, the effect of high glucose conditions was also measured on H292 and H1650 cell lines. Acidic pH, high and low glucose conditions were observed to have no effect on the motility, EMT and stemness of H1650 cell line. Hence, use of this cell line was discontinued and no further treatment conditions were tested on this cell line. In H292 cell line, acidic pH, low glucose and tumor like conditions combined together (acidic pH + low glucose + hypoxia) [AP+LG+HYP] significantly decreased motility whereas hypoxia significantly increased the motility of H292 cells. High glucose did not affect the motility of H292 cells. Although N-cadherin, a mesenchymal marker, expression was significantly upregulated by acidic pH, high and low glucose conditions, no direct correlation was observed between N-cadherin expression and motility. E-cadherin expression was not affected by acidic pH, high and low glucose conditions. An increase in N-cadherin expression and no change in E-cadherin expression under these conditions might be an indication of partial EMT. Hypoxia and AP+LG+HYP did not alter the expression of E-cadherin and N-cadherin. Although expression of vimentin, another mesenchymal marker, and Sox2, a cancer stem cell marker (CSC), was observed at the mRNA level, no expression of vimentin and Sox2 proteins was observed in H292 cells under any of these treatment conditions. The expression of OCT4, another CSC marker, was also not observed at the protein level in H292 cells. HIF-1α expression was observed in H292 cells under normoxic conditions and was unaffected by hypoxia and AP+LG+HYP. Therefore our research indicates that the effect of these TME conditions might be different on different cancer cell lines or cancer types. Not all cancers may depend on EMT for metastasis. An increase in metastasis under hypoxia may be independent of HIF-1α.
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Almurshedi, A. "Development of Afatinib lipid nanoparticles targeting non small cell lung cancer." Thesis, Liverpool John Moores University, 2018. http://researchonline.ljmu.ac.uk/9111/.
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Lung cancer is the most common cause of cancer-associated mortality in males and females globally. Widespread research is currently focused on the development of novel approaches for targeting non small cell lung cancer with different therapeutic nanotechnologies. In this study, a sensitive and selective HPLC method was developed for the quantification of afatinib (AFT) in formulations. Novel drug delivery systems based on cationic (CL) and pH-sensitive liposomes (PSL) for AFT were developed, with different ratios of lipid to AFT, using a film hydration method. The obtained liposomes had a small particle size of less than 50 nm with a low polydispersibilty index and acceptable zeta potential. The highest Encapsulation Efficiency (EE%) of AFT reached 43.20%, 50.20%, and 52.01% for NL (Non targeting liposomes), PSL, CL, respectively at the 1:0.5 ratio of AFT: lipids. The in vitro release study confirmed that all formulations had sustained release profiles in pH 7.4. However, in acidic pH values, PSL exhibited fast release. The stability study, conducted at 4°C and 25°C for 1 month, showed that the characteristics of liposomes in liquid form did not change significantly over this period. In vitro cytotoxicity studies revealed high antitumor activity of PSL on all cell lines at 0.75 μM concentration after 24 h exposure, based on using the Annexin V assay. A proteomics study identified 12 proteins which can be used as biomarkers capable of prediction of treatment response and choice of therapy for two different types of human NSCLC cells (H-1975 and H-1650). Spray drying was used to produce nanocomposite microparticles (NCMPs) using L-leucine and coated using different ratios of chitosan for the optimized PSL NPs. The particles had a corrugated surface except at high CH ratios, where more homogenous and smooth particles with some small indentations were obtained. The powder properties showed good flow properties and reproducible size. Coated NCMPs showed a delayed drug release profile compared to PSL NPs and the best correlation with the Higuchi model. A stability study at 40°C/ 75% ± 5% relative humidity (RH) showed large changes in the drug content for all coated NCMPs powders. Analysis of the in vitro aerosolization performance demonstrated a mass median aerodynamic diameter (MMAD) of 3.24 – 5.85 μm and fine particle fraction (FPF%) of 54.20-33.66%. The particle size of the reconstituted powders was ˂ 100 nm, which is within the size range to be effectively taken up by tumor cells. Assessment of the stability of spray dried liposomes after 3 months of storage at 40 °C/75% RH, showed that fusion and aggregation of the liposomes occurred in all samples tested. The C1NCMPs (lipid: LEU: CH ratio of 1:1.5:0.5) exhibited the highest FPF (51.2%) and fine particle dose (FPD) (40.0 μg of AFT) indicating deep lung deposition. Further cell viability studies of C1 NCMP, at a concentration of 0.75 μM on H-1975 NSCLC cell line showed a good toxicity profile comparable to PSL nanoparticles (NPs). The obtained data indicates that pulmonary delivery of PSL NCMPs is a potential new clinical strategy for better targetability and delivery of AFT for the treatment of lung cancer.
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Cahill, Fiona. "The role of LKB1 (STK11) in non-small cell lung cancer." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:a3162d1b-96d3-4420-82eb-e261c9732f33.
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LKB1 is the second most commonly altered tumour suppressor gene in lung adenocarcinoma, the most prevalent form of lung cancer. LKB1 is a "master kinase" that has been shown to phosphorylate up to 13 downstream targets. We hypothesised that LKB1 loss is associated with an increased dependency on alternative, targetable pathways. The overall aims of this project were to better understand the role of LKB1 loss in lung cancer and to identify novel approaches to selectively target LKB1 mutated cells. We generated isogenic cells with or without LKB1 and used these to study the effect of LKB1 on cell proliferation. Importantly, we used a range of models including 2D culture, 3D spheroids and, sub-cutaneous and orthotopic xenograft models. To understand the role of LKB1 loss in lung cancer, the effect of LKB1 on mRNA expression was analysed using whole genome RNA Sequencing. To identify novel approaches to selectively target LKB1 mutated cells, we used biological screening methods and also investigated the effect of several metabolic inhibitors. We found that loss of LKB1 expression had no effect on cell proliferation in 2D culture, but was associated with increased growth in 3D spheroids, sub-cutaneous and orthotopic xenografts, as well as greater metastasis in a lung orthotopic model. Gene ontology analysis of the transcriptome identified that genes associated with cAMP signalling and cytoskeletal organisation were differentially expressed between LKB1 deficient and proficient cells. We confirmed that cAMP signalling was increased in LKB1 deficient cells, though there was no difference in sensitivity between LKB1 deficient and proficient cells to cAMP signalling modulators. The bioactive small molecule screen showed that LKB1 deficient cells underwent apoptosis more slowly and therefore, were less sensitive to many compounds, compared with LKB1 proficient cells. Screening in 3D spheroids was a novel approach that we used to identify microtubule inhibitors as potentially selective compounds acting in LKB1 deficient cells. Our RNASeq data suggests that there was a metabolic shift from oxidative phosphorylation to aerobic glycolysis in LKB1 deficient cells, although this did not affect sensitivity to complex I inhibitors. Importantly, LKB1 deficient cells were more sensitive to glucose and glutamine deprivation which suggests that targeting these metabolic pathways may hold the greatest promise to selectively inhibit proliferation in LKB1 mutated cells.
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Ranbaduge, Nilini Sugeesha. "Mass Spectrometry-Based Clinical Proteomics for Non-Small Cell Lung Cancer." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1469103007.
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Shoji, Tsuyoshi. "Clinical Significance of p21 Expression in Non-Small-Cell Lung Cancer." Kyoto University, 2003. http://hdl.handle.net/2433/148460.
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Baker, Amanda F., Neale T. Hanke, Barbara J. Sands, Liliana Carbajal, Janet L. Anderl, and Linda L. Garland. "Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models." BioMed Central, 2014. http://hdl.handle.net/10150/610318.
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BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.
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Chu, Ka-wan Kevin, and 朱嘉運. "High-throughput molecular characterization of human non-small cell lung carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B4501288X.
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Spencer, Isaac. "Characterising PD-L1 expression in circulating melanoma and non-small cell lung cancer cells." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2020. https://ro.ecu.edu.au/theses/2318.
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Incidence rates for both melanoma and non-small cell lung cancer (NSCLC) have risen in recent decades. While advanced cases of both diseases have previously demonstrated low survivability, novel therapies such as immune checkpoint inhibitors, have significantly improved the outcome of patients suffering from these cancers. Recent clinical trials have led to the United States Food and Drug Administration (FDA) approving the use of antibodies targeting the PD-1 immune checkpoint for both melanoma and NSCLC. Anti-PD-1 antibodies have been seen to illicit responses in up to 40% of patients, however, particularly for melanoma, there is a lack of biomarkers to select for patients likely to respond.
PD-L1 expression in tumour tissue is the most studied biomarker of response to anti-PD-1 therapy in melanoma patients and is also the biomarker currently in use as a companion diagnostic test for NSCLC patients. It is believed that circulating tumour cells (CTCs) that break away from the tumour and enter the bloodstream, would share the same immune escape mechanisms as the parent tumour, and so would express PD-L1 in the same way as the tumour. Therefore, we postulate that these cells provide an accessible tumour sample for analysis of PD-L1 expression.
A previous study by our group used multi-marker flow cytometry to evaluated PD-L1 expression on CTCs from melanoma patients commencing anti-PD-L1 therapy. Here, the PDL1 expression on CTC from the latter study was compared to PD-L1 expression in matched tumour tissues. Moreover, this study describes the establishment of methodologies for immunocytochemistry analysis and scoring of PD-L1 expression on melanoma CTCs and on carcinomas CTCs, including NSCLC. Cell lines representing negative, low and high PD-L1 expression were identified to serve as controls, again for both melanoma and carcinomas. To further evaluate our methods, CTCs were extracted from the blood samples of patients with melanoma and NSCLC using microfluidic devices and immunostained to investigate the expression of PD-L1. Finally, comparison between CTC and tumour tissue PD-L1 expression was carried out in a small number of cases.
Overall, this study successfully developed immunocytochemistry protocols to effectively identify and score PD-L1 expression on both melanoma and carcinoma CTCs, thus providing a basis for further work to evaluate the clinical potential of CTCs.