Molecular determinants of therapeutic response to targeted therapies in metastatic colorectal cancer

© 2011 Dr. Andrew James WeickhardtGiven the high cost, optimizing survival of patients with colorectal cancer requires research into two important questions. Firstly, can there be improved efficacy of these agents by using novel combinations with existing or other new drugs? Secondly, what are the mechanisms of both innate and acquired resistance to these drugs? Restricting use from those patients who have factors that govern immediate innate resistance will enrich and maximise initial response rates (RR). Identification of mechanisms governing acquired resistance may allow novel future strategies to avoid these mechanisms and allow ongoing durable responses to therapy. This thesis aims to explore methods of optimizing the targeted treatment of the EGFR pathway and the VEGF related pathway in colorectal cancer. The biology of each pathway will be reviewed. Therapeutic options for inhibiting these pathways in colorectal cancer will be discussed, focusing on targeted agents. The concept of maximising the effect of targeting the EGFR pathway by using two drugs that target the same pathway will be reviewed. Additionally, biological characteristics of the tumour that may predict resistance and response to targeting each individual pathway will also be reviewed