Clinical Studies of Antisense Oligonucleotides for Cancer Therapy

Until now, the clinical demise of cancer has relied on surgical resection and the inhibition of tumor cell proliferation using ionizing radiation or chemotherapeutic drugs designed to perturb DNA synthesis or the mitotic event. The development of cytotoxic agents has resulted in improvements in the treatment of leukemia, lymphoma, testicular cancer, and many other solid tumor types. Hormone-based drugs have also been useful for breast and prostate cancers. Although much success has been achieved, cytotoxic modalities walk the therapeutic tightrope of toxicities to normal tissues vs cancer cells, and drug resistance is generally present de novo or develops with treatment. Over the last decade or so, more attention has been focused on different therapeutic approaches. These include the development of monoclonal antibodies (MAbs) to specifically target cancer cells, and small molecule-inhibitors of cell-signaling pathways that have been linked to oncogenesis or maintenance of the malignant phenotype. For example, the former approach has seen the development and licensing of Herceptin(R) (trastuzumab; Genentech/Roche), a humanized MAb that targets erbB2/HER2, a receptor tyrosine kinase that is overexpressed in some 30% of breast cancers and has shown promising clinical activity when used in combination with other drugs for the treatment of metastatic breast cancer. Promising small-molecule inhibitors of cell-signaling pathways include Gleevec trade mark (STI571, imitanib mesylate; Novartis) and Iressa trade mark (ZD1839, gefitinib; AstraZeneca). Gleevec is a small-molecule inhibitor (a phenylaminopyridine) of the tyrosine kinase encoded by the abl gene. In chronic myelogenous leukemia (CML), a chromosomal translocation forms the Philadelphia chromosome that expresses a bcr/abl gene resulting in the expression of a constitutively active Abl tyrosine kinase. Gleevec has shown excellent clinical activity against CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Gleevec is not uniquely selective for inhibition of Abl tyrosine kinase and has additional inhibitory activities against the c-Kit receptor tyrosine kinase and the platelet-derived growth factor receptor tyrosine kinase. Resistance to Gleevec characterized by overexpression or mutations in the bcr/abl gene is now emerging.