Targeted Therapies for Cancer 2004

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)—and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment—are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non–small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer. The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients. The regulatory approvals of trastuzumab (Herceptin), imatinib mesylate (Gleevec), and cetuximab (Erbitux) for patients with HER-2/neu overexpressing breast cancer, bcr/abl translocation–positive chronic myelogenous leukemia (CML), and epidermal growth factor receptor (EGFR)-overexpressing colorectal cancer, respectively, have headlined the considerable public interest in new targeted anticancer drugs. 1-3 In addition, a large number of new targeted therapies for patients with cancer, including additional small-molecule tyrosine kinase inhibitors, antisense messenger RNA inhibitors, and antibodies are in both early and late stages of clinical development. Many scientists, clinicians, and pharmaceutical company executives believe that during the next 5 to 10 years, the integration of molecular oncology and molecular diagnostics will further revolutionize oncology drug discovery and development; customize the selection, dosing, route of administration of previously approved traditional agents and new therapeutics in clinical trials; and truly personalize medical care for patients with cancer. 4-7