title: Rationally designed treatment for metastatic colorectal cancer: current drug development strategies.
abstract: The therapeutic landscape of metastatic colorectal cancer (mCRC) has changed substantially with the emergence of new molecularly targeted agents (MTA) used as single agents or alongside standard chemotherapy. The use of these MTAs extended the overall survival of patients with mCRC to a level that current chemotherapeutics alone could not achieve. In addition, improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC and MTAs have been found to have a significant role here too, as they aid resectability. However, for the majority of patients, mCRC remains an invariably incurable disease necessitating continued courses of combined treatment modalities. During the course of these treatments, either cytotoxic or biological, cancer cells maintain their ability to acquire mitogenic mutations which render them resistant to treatment. Key challenges remain to identify appropriate subsets of patients who will most likely benefit from these new MTAs and effectively select these based on validated biomarkers. Moreover, better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments, so that we can maximise the survivorship of mCRC patients. This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.
authors.affiliation: Pavlina Spiliopoulou, Hendrik-Tobias Arkenau, Drug Development Unit, Sarah Cannon Research Institute United Kingdom, London W1G 6AD, United Kingdom.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Spiliopoulou
authors.affiliation: Pavlina Spiliopoulou, Hendrik-Tobias Arkenau, Drug Development Unit, Sarah Cannon Research Institute United Kingdom, London W1G 6AD, United Kingdom.
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Colorectal cancer; Drug development; Molecularly targeted therapies