Target Identification

Some of the problems of target identification in cancer are illustrated by considering kinases, regulatory enzymes that are integral to most signaling events inside cells. In cancer, these may be either pivotal or permissive for the pathogene-sis of the malignant phenotype.2 Pivotal kinases are often critical to tumor growth and maintenance and may be subject to activation by mutation, gene amplification, or translocation (i.e., p210BCR-ABL in chronic myeloid leukemia), whereas permissive kinases are not mutated or amplified but still may have a role in signal transduction pathways important in neo-plastic growth. One of the challenges has been to identify pivotal kinases for anticancer drug development and to select patients with aberrations in these critical signaling pathways for inclusion in early clinical trials. To do this, robust biologic assays are required that will readily identify potential targets in cancer cells.

High-throughput screening using cDNA microarrays and techniques such as comparative genomic hybridization have been extensively employed to analyze gene expression in human tumors, thereby identifying novel targets for therapeutic drug development.3 Target identification and validation have been supported by tissue microarray profiling that allows the analysis of DNA, RNA, or protein levels in thousands of tumor specimens at a time to identify the frequency of molecular alterations in a population of patients with a given cancer type. In future, complex proteomic techniques using mass spectrometry will allow the identification of potential protein drug targets that are differentially expressed between tumor and normal tissue. Preclinical studies are important to determine what a gene product-protein target does in the cell, and moreover what the consequences are of inhibiting its expression or function, respectively. The technique of synthetic short interfering RNAs (siRNA) that lead to the degradation of complementary mRNA, thereby silencing gene expression, is a helpful new tool in analyzing the functional significance of certain gene products. Similarly, high-throughput screens using siRNAs in mammalian cells are in progress to identify molecular regulators that are involved in the acquisition of the malignant phenotype and also in the development of drug resistance.

TABLE 5.1. Targets for the development of novel anticancer therapies.

Molecular target

Anticancer therapeutic strategy

Tumor type and stage of clinical development

Steroid hormone receptor ER AR

Growth factor receptor EGFR

HER2 Oncogenic kinase BCR-ABL

Signal transduction pathway Ras

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