Genetics and new approaches to cancer therapy

The past two decades have been golden years for the genetics of cancer. It has become clear through the work of countless laboratory groups that both inherited and sporadic cancers arise through defects or misregulations of their genomes. Several dozen dominantly acting oncogenes have been identified, shown to be deregulated in human tumors and to positively influence one or another aspect of tumor development or behavior in experimental systems. A smaller, but still substantial, number of recessively mutated tumor suppressor genes have also been identified which, in defective form, predispose to malignancy, both in people and in genetically manipulated rodent models. The cartography of the order, accumulation and interactions of genetic lesions during tumor initiation and progression has reasonable detail for many human tumor types. Such information is proving to be tremendously valuable in diagnosis and in grouping patients into prognostic categories. There is every reason to believe that the continued use of increasingly sophisticated genomic and proteomic technologies will add another order of magnitude to the precision of such conclusions. One of the major reasons to have embarked on this sifting through the genomes of tumor cells has been the belief that tumor-specific defects will provide safer and more effective targets for therapy. While progress in this arena has been somewhat slower in pace, there are several examples now, such as drugs or antibodies targeting HER2, Bcr-Abl or the wild-type epidermal growth factor (EGF) receptor, to raise cautious optimism for the validity of this belief. It is now conceivable that future therapies will select combinations of drugs tailored to individual tumors and targeting with exquisite specificity different players in the same metabolic pathways or different pathways altogether. There are obvious advantages to such approaches: (i) the tumor-specificity of the targets should lead to a greater therapeutic window and less toxicity; (ii) the use of combination therapies may limit acquired resistance; and (iii) many of the defective pathways in tumor cells also affect drug or radiation sensitivities so that combined therapies using conventional and designed agents may be especially effective. In this Commentary, I would like to use an example from our own work to illustrate how basic genetics can lead to the identification of such a tumor-specific target, understanding of its mechanism of action and informed creation of therapeutics specifically aimed at it. This work has focused on the role of