Therapeutic Targets

The examples cited previously of directed therapies specific for a particular protein or a mutation therein are likely to grow rapidly in number as new agents and new targets are identified. One consequence of the widespread use of molecular biologic methods in the analysis of cancer tissue is the increasing awareness of recurring patterns of genes or proteins preferentially expressed by certain types or classes of tumors. Examples are illustrated in more detail later in the discussion of technologies used to identify these genes, but here we focus instead on the consequence of their identification.

Although identification of mutated kinases has captured the imagination of oncologists and cancer biologists, the reality is that mutations are commonplace in cancer, and the consequences of these mutations are widespread in all forms of cancer. As a general rule, proliferation in cancer cells is increased for lack of cell-cycle control, and apoptosis is inhibited for lack of a viable apoptotic pathway in many cancer cells. The causes of this are too numerous (and often unknown) to document in detail here. Rather, it is fair to state that no one defect explains enhanced cell proliferation and diminished apoptosis in cancer. Thus, a comprehensive analysis of contributing genes to both processes, both promoting and suppressing, can identify potential therapeutic targets, if the gene or its protein product is a druggable target. Receptor tyrosine kinases are obvious examples, based on prior comments, and so are cell-cycle regulatory genes such as MDM2 and P53, as well as a huge number of other genes involved in one or another aspect of these two basic defects in cancer cell control. Thus, adenoviral-mediated p53 replacement therapy has been explored in lung and head and neck cancer for many years,11,12 and recently Roche has developed an MDM2 inhibitor for those tumors with unopposed MDM2 activity.13 In a broader sense, gene targets identified by a variety of biologic and genomic studies have also promoted development of agents that selectively inhibit tumor characteristics, such as their ability to promote angiogenesis to develop a vascular supply necessary for growth beyond microscopic tumorlets. In this case, at least five compounds that target the vascular endothelial growth factor, VEGF, or its receptor, FLT1, have been developed to specifically inhibit angiogenesis in cancer.14,15 Early clinical results are promising but it is too early to draw conclusions.

In general, it should be apparent that the more one knows about a given cancer, the more precisely it can be targeted with therapeutics intended to exploit features unique to that tumor. In the future, the list of candidate targets is likely to expand far beyond the current short list of kinase inhibitors, monoclonal antibodies against receptor tyrosine kinases (e.g., Herceptin for HER/neu amplified breast cancer), and angiogenesis inhibitors. Proteasome inhibitors are currently being evaluated, for example,16,17 while many other candidate targets remain to be exploited, individually (integrins such as the vitronectin receptor, alpha V beta 3, for example)18 or as a class (of which there are many).19

In view of these concerns, it is reasonable to examine the contributions of molecular technologies to the characterization of cancer, and ultimately the choice of therapy, based on knowledge of candidate targets amenable to targeted therapies such as these.

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