Mechanisms of Toxicities Associated With Targeted Therapy

Introduction

Over the last several years, molecularly targeted therapy has emerged as a new generation of cancer treatment and has been integrated into treatment protocols of many hematologic and solid tumors, either as monotherapy or in combination with chemotherapy. In general, targeted therapies include monoclonal antibodies and small molecule inhibitors that specifically affect the activity of genes or proteins mediating carcinogenesis. As described by Hanahan and Weinberg, cancer cells gain several hallmark features as they develop into invasive tumors. The acquisition of these features is achieved by deregulation of physiologic pathways for proliferation, growth, apoptosis, and angiogenesis. This is achieved mainly by genetic or transcriptional alterations, including chromosomal translocations, somatic mutations, gene amplification, overexpression, and/or downregulation of target proteins or enzymes. Understanding of the molecular events underlying the process of tumorigenesis, coupled with the advent of advanced testing options, has allowed the specific targeting of cancer cells harboring such alterations and the sparing of normal cells lacking them. This has translated into the development of several targeted therapy agents which have become integral parts of cancer treatment. Imatinib inhibits BCR-ABL translocation and is the prototype of successful application of targeted therapy in chronic myelogenous leukemia (CML) ( Fig. 12.1 ). This chapter will introduce molecular targets and their mechanisms of deregulation in cancer as they relate to the development of toxicities.