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Title: The old and the new : mouse models for evaluating the therapeutic margin of radiation in lung cancer
Author: Lourenco, Luiza Helena Madia
ISNI:       0000 0004 6493 9754
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Background: Radiotherapy is widely used in the treatment of lung cancer, with both curative and palliative intent according to the stage of the disease. The tumour control potential of radiotherapy is limited by the induction of side effects; in the case of thoracic radiotherapy (tRTX), common side effects are oesophagitis, pneumonitis and pulmonary fibrosis. The main challenges in the field are, therefore, to find ways to increase tumour killing and/or decrease normal tissue toxicity, to improve the therapeutic margin of radiation. Aims: Firstly, to characterise selected early and late tissue responses in a mouse model of tRTX. Secondly, to investigate approaches to improve the therapeutic margin of tRTX by modulating the inflammatory response or the DNA damage response (DDR). Methods: To evaluate normal tissue responses, we used tRTX of C57BL6 mice, a well-established preclinical model of radiation-induced pulmonary fibrosis. In parallel, human lung cancer cells were grown as subcutaneous xenografts in immune compromised nude mice, and used to evaluate anti-tumour responses. A/J mice bearing urethane-induced lung tumours were used to evaluate normal and tumour lung tissue responses simultaneously. Immunohistochemistry, western blotting and non-invasive imaging were used to assess treatment responses. Results: Acute and transient local (neutrophil lung infiltration) and systemic (plasma levels of pro-inflammatory cytokines) inflammatory/immune responses were induced by tRTX. Thoracic radiation induced DNA double-strand breaks in lung tissue, a proportion of which were persistent. Fractionation schedules of tRTX led to pneumonitis and pulmonary fibrosis. Knock-out of myeloperoxidase activity was associated with decreased early and late normal tissue responses to tRTX. In separate mouse models, we observed that DDR inhibitors effectively radiosensitised xenograft tumours, but differentially affected thoracic normal tissues. PARP inhibition in combination with tRTX lead to oesophagitis whereas ATM inhibition increased radiation-induced lung damage. Using the A/J strain, we simultaneously evaluated normal and tumour lung tissues responses to tRTX, establishing a novel mouse model for the study of therapeutic index. In the A/J model, ATM inhibition in combination with tRTX showed significant anti-tumour activity, but was also associated with increased late normal tissue effects. Conclusions: Myeloperoxidase contributes to early inflammatory responses and late effects induced by tRTX. DDR inhibitors have similar tumour responses but differential normal tissue responses when combined to tRTX. A newly established A/J mouse model has the potential to have a significant impact on studies evaluating the therapeutic index of novel therapies in combination with thoracic radiation by allowing for the simultaneous assessment of normal and tumour lung tissues in the context of a fully functional immune system.
Supervisor: Ryan, Anderson Sponsor: CNPq - Brazilian Government
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available