Using GEMMs to investigate novel therapeutic strategies for colorectal cancer

摘要: Despite recent advances in the clinic to integrate novel targeted therapeutic agents into standard therapy, colorectal cancer (CRC) remains a significant cause of mortality. The high attrition rate compounds at phase III clinical trials for CRC, has been attributed limited information from pre-clinical strategies, particular, use inadequate xenograft models. In response, this thesis aimed utilise robust and relevant genetically engineered mouse models CRC evaluate number strategies. Whilst mutations tumour suppressor APC are crucial initiation which lead activation PI3K MAPK signalling pathways, such as through loss protein PTEN oncogenic KRAS, have implicated promoting progression CRC. As such, combinations these genetic alterations within murine intestine, using Cre-LoxP system, differing invasive intestinal adenocarcinoma. This reports targeting pathways dual mTOR inhibitor NVP-BEZ235, MEK MEK162, respectively. For this, were initially evaluated pharmacodynamic anti-tumour effects short term exposure experiments. These analyses yielded range effects, some appeared predictive long efficacy, others contradictory revealed feedback mechanisms. Furthermore, assessed setting effect continuous treatment on longevity burden Here, whilst PI3K/mTOR inhibition significantly increased all models, was only effective Apc Kras mutant settings, identifying Pten marker non-response inhibition, independently also setting. analysis combination therapy settings identified scheduling be key achieve concomitant pathway particularly deficient Ultimately, when setting, although displayed no further benefit had additive benefits synergistic setting. Nevertheless despite promise chemotherapeutic 5-flurouracil (5-FU) remain backbone regardless moderate 10-15% advanced settings. resistance 5-FU predominantly upregulation enzyme thymidylate synthase (TS) frequently 2 occurs human tumours. Investigations reported here target tumours with upregulated TS analogues anti-viral agent Brivudin (BVDU), metabolites converted anti-cancer by TS. Initially, vitro characterisation small library potent compounds. Following evaluation model adenocarcinoma, two compounds: CPF472 CPF3172 taken forward Subsequently, study showed efficacy setting. Taken together, investigations presented highlight utility appropriate evaluating strategies generating clinically hypotheses.