Until the 1990s, cytotoxic
chemotherapy has been the cornerstone of medical
therapy for gastrointestinal (GI)
cancers. Better understanding of the
cancer cell molecular biology has led to the therapeutic revolution of targeted
therapies, i.e.
monoclonal antibodies or small molecule inhibitors directed against
proteins that are specifically overexpressed or mutated in
cancer cells. These agents, being more specific to
cancer cells, were expected to be less toxic than conventional
cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive
biomarkers of response to these
therapies. Targeted agents have provided clinical benefit in many GI
cancer types. Particularly, some GI tumours are considered chemoresistant and targeted
therapies have offered a new therapeutic base for their management. Hence,
somatostatin receptor-directed strategies,
sorafenib, and
imatinib have revolutioned the management of neuroendocrine tumours (NET),
hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive
biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI
cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted
therapies.