Combining Targeted Therapies

Abstract

Many new agents have emerged in the drug development pipeline that target the mechanisms driving the development and progression of specific cancers. Ultimately, the goal is to create personalized treatment plans for each patient’s tumor(s). Despite promising early preclinical data, only a handful of the targeted molecules developed thus far have shown benefit when used as single agents. The need to combine individual agents with existing therapies or in novel combinations has become increasingly important. A primary objective is to design drug combinations that can overcome drug resistance. Cross talk among signaling pathways and parallel pathways that contribute to tumor pathogenesis is thought to contribute to single-agent resistance. Combining cytostatic and cytotoxic therapies with targeted agents could help overcome resistance or prevent its development. The issues surrounding the combinatorial approach that are covered in this chapter are patient selection, toxicity profiles from additive and synergistic effects of combining chemotherapy with targeted therapy, and the importance of timing when combining targeted therapy with cytotoxic chemotherapy. The variables that need to be considered when designing effective combinations of targeted agents are discussed. Finally, the chapter looks at ways to improve preclinical models. Sophisticated technologies, including microarray technologies leading to genomic profiling through gene set enrichment analysis (GSEA) or reverse phase array (RPPA) proteomic technology, which evaluates microarry data at the level of the gene and protein, are also covered along with the experience that investigators have had with various targeted agents that have been tested in preclinical and clinical studies, including trastuzumab, epithelial growth factor receptor tyrosine kinase inhibitors, sorafenib and its combinations, and others.