Non-Small-Cell-Lung Cancer (NSCLC) patients with mutations in EGFR have greater response rates and survival when treated with the tyrosine kinase inhibitor erlotinib. To elucidate how erlotinib inhibits EGFR, this study included: 1) inhibiting an EGFR mutant cell line to reveal EGFR regulated phosphotyrosine (pY) sites; 2) comparing erlotinib sensitive and insensitive cell lines to reveal functionally important pY sites; 3) revealing novel pY sites. Observations were collected using the LTQ-Orbitrap mass spectrometer. This study identified five new EGFR regulated pY sites and five pY sites that correlated with erlotinib sensitivity; the majority of them are related to cell-cell interactions. By comparing all observed pY sites to the Phosphosite and PhosphoELM database, our results included 67 unregistered sites. This study has identified novel biomarkers and potential therapeutic targets, many of which were associated with cell migration and adhesion function. Further functional validation is necessary.

Yearly, 22, 200 Canadians are diagnosed with lung cancer, with 80-85% of the cases being non-small cell lung cancer (NSCLC). With diagnoses being predominantly in the advanced stages, prognosis is poor and quality of life (QoL) becomes the focus of treatment. The main symptom cachexia, issues a loss of strength and impacts on an important aspect of QoL, physical function. Physical function is predominately assessed subjectively. Lately performance-based measures are gaining in popularity. One performance measure, the chair rise test, has not been validated in the NSCLC population and was the objective of this study. / Subjects completed the chair rise test, 6MWT, hand grip, and the SF-36 pre and post chemotherapy. Evidence for construct and discriminant validity but not predictive validity was provided for the chair rise test. The 60-second chair rise may be too strenuous for persons with severe disability but a standardized timed-based chair rise test is needed.

Background: Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of a medical treatment. However, the efficacy demonstrated by trials does not automatically translate into a comparable level of effectiveness in the real world. RCTs may vary from routine clinical practice in several ways; the patients themselves, the delivery of the treatment, and the collateral care provided during treatment. Phase IV studies that assess outcomes of a treatment in the real-world provide a mechanism for assessing treatment effectiveness. Objectives: The objectives of this study were to: describe the characteristics of patients receiving standard, first-line, palliative, platinum-doublet chemotherapy (PPDC) for non-small cell lung cancer (NSCLC) in routine care; describe the effectiveness of PPDC in terms of wellbeing and symptom control; identify patient characteristics associated with change in wellbeing with treatment; and compare reported treatment efficacy to the effectiveness observed in the current study. Methods: This study was a retrospective cohort study of patients treated at Ontario’s Regional Cancer Centres (RCCs). Patients’ Edmonton Symptom Assessment System (ESAS) scores were used to describe patients’ symptomatic status and wellbeing. The proportions of patients whose wellbeing improved, remained stable or deteriorated at two months were calculated. Using logistic regression, patient and disease characteristics were assessed for association with change in wellbeing at two months (dichotomized as improved/stable and deteriorated). In comparing trial results to this study, adjustments were made for differences in case mix. Results: Patients’ median age was 65, 55% were male and the majority had stage IV disease and adenocarcinoma histology. Patients’ baseline wellbeing and symptomatic status varied widely. 61.3% (95% CI: 55.8 – 66.6%) of patients had improved or stable wellbeing at two months. Histology and baseline wellbeing score were associated with change in wellbeing at two months. The case mix adjusted estimates of the proportion of improved/stable patients (60.0% (95% CI 54.5 – 65.3) and 60.5% (95% CI 54.9 – 65.6)) were consistent with the proportion of patients achieving general quality of life improvement or stabilization in RCTs (55% and 63%). Conclusion: The effectiveness of PPDC delivered in Ontario’s RCCs is consistent with that expected based on the results of RCTs. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-04-23 11:53:33.491

Lung cancer is the most common cancer worldwide and is the fourth leading cause of death in South Africa. Lung cancer is categorised into two types; non-small cell lung cancer and small cell lung cancer (SCLC). SCLC constitutes 20% of all lung cancers and is considered to be an aggressive tumour as it gains chemo-resistance and exhibits early metastasis in diagnosed patients. SCLC cells originate from the neuroendocrine cells of the bronchoepithelium and are known to secrete the neuropeptide, proopiomelanocortin (POMC). POMC undergoes proteolytic cleavage to produce the adrenocorticotropin hormone (ACTH). ACTH stimulates the production of the steroid hormone, glucocorticoid hormone (GC), through the hypothalamus-pituitary-adrenal (HPA) axis. The produced GCs mediate a negative feedback system of the HPA axis to sequester ACTH production. SCLC cells are insensitive to this negative feedback stimulus. GCs elicit their actions through the glucocorticoid receptor (GR). Studies have shown that SCLC cells have a reduced expression of GR which perpetuates the GC-insensitivity. Importantly, over-expression of exogenous GR in SCLC cells leads to cell death by apoptosis. It was postulated that SCLC cells select against GR expression for longevity. Cancer cells are known to alter/silence the expression of tumour suppressor genes by a mechanism known as methylation. Methylation occurs when the enzyme, DNA methyltransferase 1, adds a methyl group to a cytosine present in a guanine-cytosine rich region of the gene (CpG island). The GR gene has a 5’-untranslated exon 1 region that consists of eight promoter regions (1A-1J), in these promoter regions are many CpG islands that have the potential to be methylated. The first aim of this study was to determine the promoter/s utilised by SCLC cells to express the GR protein. Conventional PCR revealed that all three cell lines predominantly utilise promoters 1B and 1C for GR expression. Bioinformatic analysis revealed that these promoters contain putative CpG islands and new data suggests that the GR is silenced by methylation and that treatment with a de-methylating agent results in GR re-expression. To determine which promoter is responsible for GR re-expression after de-methylation, the SCLC cell line, DMS79, as well as two control cell lines, A549 and HEK cells, were treated with the de-methylating agent, 5-aza-2’-deoxycytidine, for 72 hours. qPCR analyses revealed that all three cell lines expressed promoters 1B and 1C with A549 cells showing no evidence of methylation. The HEK cells showed methylation in promoter 1C and not promoter 1B. The SCLC cells showed methylation in both promoter 1B and 1C, however, only promoter 1B showed a significantincrease in transcript levels. SCLC cells are induced to undergo GC-mediated apoptosis when GR expression is restored however the mechanism utilised by the GR to induce the apoptotic cascade is unknown. The GR structure is divided into three domains; ligand binding domain (LBD), DNA binding domain (DBD) and amino terminal domain (NTD). The second aim of this study was to determine the component of the GR that induces apoptosis of SCLC cells. HEK and SCLC cells were infected with empty virus and various GR construct viruses; containing either a wild-type GR, ligand binding mutant, DNA binding mutant or a transactivation mutant (NTD); for 72 hours. Both cell lines were quantified for apoptosis and cell death using microscopic analyses. In HEK cells, it was shown that apoptosis occurred in cells expressing the wild-type GR, the DNA binding mutant and transactivation mutant constructs but apoptosis was reduced in cells expressing the ligand binding viruses. This indicates that the LBD may be necessary for inducing apoptosis in HEK cells. In DMS79 cells, apoptosis occurred in cells expressing the wild-type GR, ligand binding mutant and the DNA binding mutant constructs. There was less apoptotic activity exhibited in the transactivation constructs which indicates the NTD may be necessary for apoptosis induction in these cells. The NTD of the GR is responsible for interaction with other transcription factors to mediate GR transcriptional activity and this study has shown that the transactivation domain plays a necessary role in apoptosis induction. An analysis of the various pathways the GR interacts with through the NTD domain could lead to the identification of the pathway which triggers apoptosis in SCLC cells. This discovery, together with knowledge of promoter methylation and expression may contribute to the development of new, more effective therapies for SCLC. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2013.

Lung cancer is the leading cause of cancer-related deaths among men and women. Non-Small Cell Lung Cancer (NSCLC) constitutes the most common type of lung cancer and is frequently diagnosed at advanced stages. In the past decade, discovery of Epidermal Growth Factor Receptor (EGFR) mutations have heralded a new paradigm of personalized treatment for NSCLC. Clinical studies have shown that molecular targeted therapies increase survival and improve quality of life in patients. Despite these advances, the realization of personalized therapies for NSCLC faces a number of challenges including the integration of clinical and genetic data and a lack of clinical decision support tools to assist physicians with patient selection. This thesis demonstrates the development of a predictive computational model for personalized therapeutic interventions in advanced NSCLC. The findings suggest that the combination of clinical and genetic data significantly improves the model’s predictive performance for tumor response than clinical data alone.

Multidrug resistance (MDR) in small cell lung cancer is one of the major causes of failures of chemotherapy. MDR is a means of protection of tumor cells against chemotherapeutic drugs. Although the molecular basis of MDR is not fully understood, genes involved in apoptosis may be mutated. Recent finding of a link between over-expression of an apoptotic gene, cyclooxygenase 1 (cox 1), and MDR suggests that cox 1 is involved in the development of MDR phenotype. This research was an attempt to observe whether up-regulation of cox 1 contributes to the MDR phenotype in small cell lung cancer cells. This research ultimately may provide a mechanism to reverse the abberant up-regulation of apoptosis genes associated with multidrug resistance to either eliminate or control reproduction of cancer cells. Real time RT PCR was used to confirm the up-regulation of cox 1 in cultured MDR resistant small cell lung cancer cells (GLC4). The up-regulated cox 1 expression was down-regulated using RNA interference technology (RNAi) by transfection with an anti-cox 1 siRNA. More than 90% transfection of cells was confirmed using confocal microscopy. Down-regulation of cox 1 was validated as the protein expression significantly decreased (P=0.004) from multidrug resistant small cell lung cancer transfected cells compared to multidrug resistant nontransfected cells. There was decrease level of expression of cox 1 in multidrug resistant cells after the knockdown with siRNA specific to cox 1. The decreased level of cox 1 expression and, therefore, Cox 1 production increased the rate of apoptosis in small cell lung cancer cells as indicated by its sensitivity to the doxorubicin. / Department of Biology

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Recent studies have suggested significant variation in radiotherapy schedules used to treat advanced NSCLC, both between different centres as well as between countries. In this study, treatment methodologies have been explored using management plans proposed by radiation oncologists when given general questions and theoretical case histories for patients with advanced NSCLC. Methods and Materials The survey was conducted by sending a questionnaire to twenty four radiotherapy centres in Europe. The questionnaire was composed of two sections. The first section concerned reasons for starting radiotherapy, parameters that influence the choice of total dose and fractionation for radiotherapy and the kind of equipment that is used. The second section examines five case histories and asked the responders about the management of these five theoretical patients also regarding the radiotherapy techniques proposed and the aim of treatment (radical or palliative). Furthermore, trials comparing different regimens of palliative radiotherapy in patients with NSCLC were compared. Nineteen trials were reviewed. There were important differences in the doses of radiotherapy investigated, the patient characteristics and the outcome measures. Results In the first part responders (70% of the centres) suggested as the most important factors that influence the choice of total dose and fractionation for radiotherapy, distant metastases, performance status of the patient, lung function and size of the primary tumour. The most common reasons for starting the treatment is not only symptom relief, but also cure and prolongation of life. In the second part, more than 95% of the responders replied that they would give radiotherapy in each of these cases. The median total doses proposed where 20Gy/5fractions/1week or 30Gy/10fractions/2weeks for cases A and D (equivalent dose for fractionation 2Gy per fraction=23 and 33Gy) and 60-68Gy/30fractions/6weeks or 68Gy/34fractions/7weeks for cases B, C and E. For case E, 20% of the responders suggested Stereotactic Body Radiotherapy with 63Gy in 3 Fractions. The total dose and number of fractions of radiotherapy could be related to the perceived aims and expectations of treatment e.g. those aiming to extent life would give significantly higher total doses in a larger number of fractions, whereas those aiming to relieve symptoms would give significantly lower total doses. For the review to the literature there is no strong evidence that any regimen gives greater palliation. Higher dose regimens give more acute toxicity, especially oesophagitis. There is evidence for a modest increase in survival (5% at 1 year and 3% at 2 years) in patients with better performance status (PS) given higher dose radiotherapy. Some regimens are associated with an increased risk of radiation myelitis. Conclusions This survey demonstrates a range of treatment strategies for advanced and inoperable NSCLC within Europe. There are a number of factors that influence the perceived aims of treatment and treatment planning. These factors should be taken into account when evaluating the effectiveness of different irradiation techniques, especially in the determination of radiobiological parameters and dose-response relations. The majority of patients should be treated with short courses of palliative radiotherapy, of 1 or 2 fractions. Care should be taken with the dose to the spinal cord. The use of high dose palliative regimens should be considered for and discussed with selected patients with good performance status. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients need to be carried out. / Πρόσφατες μελέτες έχουν αναδείξει σημαντική ποικιλία στα ακτινοθεραπευτικά σχήματα που χρησιμοποιούνται στην ακτινοθεραπεία του μη μικροκυτταρικού καρκίνου του πνεύμονα προχωρημένου σταδίου. Στη συγκεκριμένη μελέτη θεραπευτικές μεθοδολογίες έχουν διερευνηθεί χρησιμοποιώντας τεχνικές που προτείνονται από ογκολόγους ακτινοθεραπευτές . Υλικά και Μέθοδοι: Η μελέτη αποτελείται από δυο μέρη. Στο πρώτο ένα ερωτηματολόγιο εστάλη σε είκοσι τέσσερα ακτινοθεραπευτικά κέντρα στην Ευρώπη .Το ερωτηματολόγιο αποτελούνταν από δυο τμήματα. Στο πρώτο ζητούνταν οι λόγοι για τους οποίους γίνεται έναρξη της ακτινοθεραπείας, οι παράμετροι που επηρεάζουν την επιλογή για τη συνολική δόση και τις συνεδρίες για την θεραπεία και τον εξοπλισμό που χρησιμοποιούν. Στο δεύτερο τμήμα παρουσιαστήκαν πέντε θεωρητικά κλινικά περιστατικά και ζητήθηκε η αντιμετώπιση αυτών των θεωρητικών ασθενών. Στο δεύτερο μέρος της μελέτης πραγματοποιήθηκε ανασκόπηση στη βιβλιογραφία και σύγκριση των αποτελεσμάτων κλινικών δοκιμών που έχουν πραγματοποιηθεί στο παρελθόν. Αποτελέσματα: Στο ερωτηματολόγιο απάντησαν το εβδομήντα τοις εκατό των κέντρων στα όποια εστάλη. Στο πρώτο μέρος ως οι πιο σημαντικοί παρόντες που επηρεάζουν την επιλογή της τελικής δόσης και τις συνεδρίες οριστήκαν οι παρουσία απομακρυσμένων μεταστάσεων, η κλινική εικόνα του ασθενούς, η πνευμονική λειτουργία και το μέγεθος του πρωτογενούς όγκου. Οι σημαντικότεροι λόγοι για έναρξη θεραπείας είναι ανακούφιση από τα συμπτώματα καθώς και επιμήκυνση της ζωής. Στο δεύτερο μέρος ενενήντα πέντε τοις εκατό των κέντρων απάντησαν ότι θα πραγματοποιούσαν ακτινοθεραπεία και στους πέντε αυτούς ασθενείς. Η επιλογή της συνολικής δόσης και συνεδρίων επηρεάζεται από την θεώρηση της θεραπείας ως παρηγορική ή θεραπευτική. Τα κέντρα που είχαν στόχο την επιμήκυνση της ζωής έδιναν μεγαλύτερες δόσεις και περισσότερες συνεδρίες εν αντιθέσει με τα κέντρα που είχαν στόχο την υποχώρηση των συμπτωμάτων που έδιναν μικρότερης δόσεις σε λιγότερες συνεδρίες. Στο δεύτερο μέρος υπολογιστήκαν οι σχετικές βιολογικές δραστικότητες από τα δεδομένα της βιβλιογραφίας καθώς και ο παράγοντας πολλαπλασιασμού του όγκου και κατασκευάστηκαν καμπύλες δόσης απόκρισης. Συμπεράσματα: Η μελέτη αποδεικνύει την ύπαρξη ποικιλίας στις τεχνικές που χρησιμοποιούνται στη θεραπεία προχωρημένου και ανεγχείρητου μη μικροκυτταρικού καρκίνου του πνεύμονα. Αυτοί οι παράγοντες πρέπει να συνυπολογίζονται όταν εκτιμάται η αποτελεσματικότητα διαφορετικών ακτινοθεραπευτικών τεχνικών, κυρίως στο προσδιορισμό ακτινολογικών παραμέτρων και σχέσεων δόσης –απόκρισης.

Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non-small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, similar to 50% of physicians reported they "definitely" or "probably" would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM.