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Assessment of the impact of deregulated signal transduction pathways on the radiotherapy response of non-small-cell lung cancer
Lung cancer is the leading cause of cancer-related death worldwide. Approximately 85 % of all lung cancers are histologically grouped as non-small-cell lung cancer (NSCLC). Besides surgery and chemotherapy, radiotherapy is firmly established as an important modality in curative treatment of localized as well as locally advanced NSCLC and in palliative care. Nevertheless, systemic and localized relapse is frequently observed. Recent developments have led to a more refined typing of advanced NSCLC by incorporating biomarkers of oncogenic pathway activation. This has allowed the successful introduction of "targeted pharmacotherapies" that are better tailored towards biological differences between histologically uniform NSCLC entities. In contrast, radiotherapy still does not take advantage of biological disease heterogeneity, and radiosensitization protocols are empirically derived, rather than based on validated biomarkers. Against this background, it was hypothesized that an improved understanding of the modulation of the radiotherapy response of NSCLC by signal transduction pathways may open new avenues for the development of more specific protocols to combine radiotherapy with pharmacotherapies. To this end, a systematic assessment of the functional impact of selected regulators of apoptosis, oncogenes, and signal transduction mediators on irradiation-induced cell death was initiated in a small-scale screen of lung cancer models. Anti-apoptotic members of the BCL-2 family have been selected as the first group of potential biomarkers for the radiotherapy response in NSCLC. BCL-xL as well as MCL-1 conferred resistance against irradiation in A431 cells. Expression of both modulators led to decreased radiation-induced cell death and additionally gave a competitive edge in clonogenic survival in vitro. Studies obtained by radiation therapy of tumor-bearing mice in vivo supported the relevance of BCL-xL for radioresistance in an organismal context. Surprisingly, these findings were not convincingly explained by ...
Assessment of the impact of deregulated signal transduction pathways on the radiotherapy response of non-small-cell lung cancer
Lung cancer is the leading cause of cancer-related death worldwide. Approximately 85 % of all lung cancers are histologically grouped as non-small-cell lung cancer (NSCLC). Besides surgery and chemotherapy, radiotherapy is firmly established as an important modality in curative treatment of localized as well as locally advanced NSCLC and in palliative care. Nevertheless, systemic and localized relapse is frequently observed. Recent developments have led to a more refined typing of advanced NSCLC by incorporating biomarkers of oncogenic pathway activation. This has allowed the successful introduction of "targeted pharmacotherapies" that are better tailored towards biological differences between histologically uniform NSCLC entities. In contrast, radiotherapy still does not take advantage of biological disease heterogeneity, and radiosensitization protocols are empirically derived, rather than based on validated biomarkers. Against this background, it was hypothesized that an improved understanding of the modulation of the radiotherapy response of NSCLC by signal transduction pathways may open new avenues for the development of more specific protocols to combine radiotherapy with pharmacotherapies. To this end, a systematic assessment of the functional impact of selected regulators of apoptosis, oncogenes, and signal transduction mediators on irradiation-induced cell death was initiated in a small-scale screen of lung cancer models. Anti-apoptotic members of the BCL-2 family have been selected as the first group of potential biomarkers for the radiotherapy response in NSCLC. BCL-xL as well as MCL-1 conferred resistance against irradiation in A431 cells. Expression of both modulators led to decreased radiation-induced cell death and additionally gave a competitive edge in clonogenic survival in vitro. Studies obtained by radiation therapy of tumor-bearing mice in vivo supported the relevance of BCL-xL for radioresistance in an organismal context. Surprisingly, these findings were not convincingly explained by ...
Assessment of the impact of deregulated signal transduction pathways on the radiotherapy response of non-small-cell lung cancer
Wieczorek, Sarah Alexandra (Autor:in) / Schuler, Martin
06.02.2018
Hochschulschrift
Elektronische Ressource
Englisch
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