The Human Genome Project has enabled sequencing of human DNA and led to advancements in technologies that detect genomic, transcriptional, proteomic, and epigenetic changes. These technologies, combined with novel drug development, have accelerated the implementation of personalized medicine. Personalized medicine uses concepts of the genetic and environmental bases of disease to individualize prevention, diagnosis, and treatment (1,2). Optimization of treatment using targeted therapy—molecules targeting specific enzymes, growth factor receptors, and signal transducers, thereby interfering with a variety of oncogenic cellular processes—and other strategies made possible by advances in translational medicine holds the promise of improving patient care (3).
This chapter focuses on targeted therapy in cancer therapeutics. The material is organized according to the key drivers of carcinogenesis in humans and summarizes the current state-of-the-art applications of personalized medicine.
Upregulation of the mitogen-activated protein kinase (MAPK) cascades RAF (rapidly accelerated fibrosarcoma) and MEK (MAPK/extracellular signal-regulated kinase [ERK]) contributes to carcinogenesis. Several cell surface molecules activate RAS (KRAS, NRAS, and HRAS), a family of guanine triphosphatases (GTPases) that activate downstream RAF protein kinases (BRAF, CRAF, and ARAF). The most important substrates of RAF kinases are MEK1 and MEK2 (MAPK/ERK kinases). The MEK kinases have one main substrate, ERK (4). Activation of ERK leads to modifications in gene expression mediated by transcription factors that control cell cycle progression, differentiation, metabolism, survival, migration, and invasion. This pathway regulates apoptosis by the posttranslational phosphorylation of apoptotic regulatory molecules (Bad, Bim, Mcl-1, and caspase 9). RAS is a downstream effector of the epidermal growth factor receptor (EGFR). Activation of ERK promotes upregulated expression of EGFR ligands and an autocrine loop critical for tumor growth (5). The frequency of molecular alterations in major pathway components is shown in the COSMIC (Catalogue of Somatic Mutations in Cancer) database (http://www.sanger.ac.uk/genetics/CGP/cosmic/).
Mutations in BRAF are found in 62% to 72% of patients with metastatic melanoma (6) and are less frequent in the radial growth phase (10%) and in situ (5.6%) melanomas (7). Mutations of NRAS occur in 5.2% of melanomas (7). In conjunctival melanoma, BRAF and NRAS mutations were identified in 29% and 18% of patients, respectively (8). Alterations of KIT were found in 36% and 39% of patients with acral and mucosal melanoma, respectively (9). Alterations of GNAQ and GNA11 were found in 45% and 32% of patients with uveal melanoma, respectively (10).
Inhibitors of BRAF and MEK have been approved by the US Food and Drug Administration (FDA) based on their significant antitumor activity and tolerability in patients with melanoma. The FDA-approved drugs and selected investigational agents by molecular target/pathway are listed in Table 49-1.
Table 49-1FDA-Approved and Selected Investigational Targeted ...