Target identification and validation

The objective is to identify genes and their cognate proteins that are directly responsible for cancer causation and progression. Having identified a gene that is either mutated or shows deregulated expression, a variety of experiments can be carried out to validate the target—that is, to provide evidence that it is indeed involved in the disease process and to increase the level of confidence that pharmacological manipulations of the target would lead to an anti-tumour effect.

The identification of new molecular targets in cancer has been revolutionized by human and other genome projects. All 30 000 human genes were published in Science and Nature in February 2001. Determining the specific involvement of various genes in human tumours requires molecular studies on familial and sporadic cancers to reveal the natural history of various malignant diseases at the genetic level. A leading example of this has been colorectal cancer, where it is now clear that genes such as APC, ras, p53, and the mismatch repair proteins play key roles.

Various techniques can be used for target validation. These include transfection, gene knock-out and knock-in, micro-injection of inhibitory antibodies, dominant negative constructs, anti-sense constructs and oligonucleotides, inhibitory peptides, and pharmacological agents, through to clinical data linking gene mutation or deregulation to clinical outcome (e.g. overexpression of EGF and erbB2 receptors in ovarian and breast cancer).

The choice of molecular target will relate to the strengths of the validation package, together with the incidence of the abnormalities in human cancer and the technical feasibility of achieving pharmacological manipulation. For example, enzymes such as kinases and proteases are more readily inhibited by drugs than are protein-protein interactions.

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