Novel Strategies to Improve the Efficacy of Anticancer Agents in Human Colorectal Carcinoma

Abstract

Colorectal cancer is one of the leading causes of cancer deaths worldwide. For decades, 5-fluorouracil has been the only effective chemotherapeutic agent for the treatment of this disease. Lately, the addition of irinotecan and oxaliplatin to standard 5-fluorouracil-based chemotherapy has improved not only response rates but also overall survival. Intense efforts have also focused on identifying novel agents targeting specific growth factor receptors, such as epidermal growth factor receptor 1 (EGFR1), which is over-expressed in a number of solid tumours of ectodermal origin, including colon adenocarcinoma, or mediators of angiogenesis, such as vascular endothelial growth factor (VEGF). Some of these molecular-targeted agents (i.e. the anti-EGFR1 monoclonal antibodies cetuximab and panitumumab, and the anti-VEGF monoclonal antibody bevacizumab) can be safely and effectively used in combination with conventional chemotherapy in colorectal cancer patients. However, recent evidence suggests that anti-EGFR1 antibodies are ineffective in tumours bearing the oncogenic activation of signalling pathways downstream of the EGFR1. Therefore, in spite of these advances, there is still a strong need for more effective and well-tolerated therapies for the management of human colorectal carcinoma. With such a perspective, this review addresses some of the critical issues under evaluation in either pre-clinical studies or clinical trials and focuses on innovative strategies for the rational combination of anticancer drugs in order to improve the synergism between traditional chemotherapeutics and novel molecular-targeted agents. Based on the evidence that colorectal cancer is characterised by the activation of survival signals responsible for protecting cells from the cytotoxic effects of anticancer agents, we discuss the role of the TNF-receptor-associated protein 1 (TRAP1)/heat shock protein 90 (HSP90) anti-apoptotic pathway, which is involved in drug resistance and may became a novel potential molecular target to improve the efficacy of drug therapies in human colorectal carcinoma.