Improvement of antiangiogenic therapies in colorectal cancer

• Autor(a) principal: Neto, João Manuel Fernandes
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/15349
• topic: Biotecnologia industrial e ambiental; Hipóxia; Cancro colorectal; Angiogénese

Angiogenesis is essential for tumor progression. Antiangiogenic therapies block angiogenesis and cause vessel regression, which leads to an increase of tumor hypoxia. Hypoxia is responsible for many effects in tumor biology, among which, the selection of cells that are more aggressive and more resistant to cancer therapies. In this project we aim to get some molecular insight on the mechanism(s) underlying the resistance to the combination of bevacizumab and cetuximab and to find synthetic lethal interactions with hypoxia. Our results show that: hypoxia induces resistance to EGFR inhibition in WT4 CRC cell; HIF1α is not driving the resistance phenotype; hypoxia activates RAS in WT4 CRC cells; MEK inhibitors increase the sensitivity to EGFR inhibitors in hypoxia and cytokines seem to be involved in the activation of RAS in hypoxia. We also identified four genes as potential candidates to be synthetic lethal with hypoxia. Our findings are of great clinical and biological significance and may lead to better combination therapies, improving current treatments for CRC patients and may also lead to the discovery of biomarkers of response to antiangiogenic therapies.