approaches are geared toward identifying ways to break tolerance or circumvent resistance mechanisms.
Recently, research has been focusing on designing antibodies to act on cell types and molecules necessary for tumor growth and on using antibodies as vehicles to carry a toxic agent to a tumor site (Dillman, 2001). Numerous approaches to cancer vaccines are also being tested (Fearon et al., 1990, Pardoll, 2002a), and the future may see more widespread use of immunotherapy in combination with other modalities: surgery plus radiation plus immunotherapy, for example. However, a major challenge in cancer vaccines remains finding strategies to break self tolerance and generate immunity through manipulating both the vaccine target (antigen) and the delivery system (Wang and Wang, 2002).
The increasingly rapid identification of specific therapeutic targets—as outlined above—and improvements in validating these targets through refined in vitro systems and more sophisticated animal models of cancer provide an important foundation for developing small molecules and other agents with the potential to be highly specific, potent, and non-toxic. And immunologic approaches are zeroing in on ways to engage the immune system very specifically against cancers.
The future development of successful agents will involve both traditional and modified high-throughput screening of very large combinatorial libraries of compounds as well as in silico molecular modeling (so-called “rational drug design”), both of which will be supported by improved and accelerated methods for determining structure-activity relationships of drug candidates.
Progress in every stage of cancer drug discovery and therapy—from target identification, to compound development, to rational treatment regimens based on precise molecular diagnoses of individual patients—is poised to provide the next generation of cancer patients, and certainly the generation after that, with far better options for eliminating or controlling their disease than exist today. The next chapters of this background paper discuss the programs of two key federal agencies for realizing those better options for cancer drug development.