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.

Keywords: Colorectal cancer; Molecularly targeted therapies; Drug development

Core tip: Abrogation of the mitogen-activated protein kinase pathway downstream epidermal growth factor receptor (EGFR) has emerged as a new potential targetable pathway in the treatment of metastatic colorectal cancer. Similarly, a variety of agents blocking the PI3K/Akt/mTOR pathway are underway. At the same time, a combinatorial inhibition of angiogenesis is being attempted with dual blockade of vascular-endothelial growth factor and c-mesenchymal-epithelial transition factor. Indications that HER-2 overactivation can confer resistance to treatment to MoAb against EGFR has revealed yet another potential target whereas PARP inhibitors are being tested for their ability to cause synthetic lethality in cancer cells with established defects in MMR system.