Biotechs Continue their Assault on Cancer
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Biotechs Continue their Assault on Cancer An Update from BIO 2004 Cancer drug development continues to be a major emphasis for biotech companies, as outlined by Hal Barron, Genentech's Chief Medical Officer, at BIO 2004.* The new wave of therapies focuses on specific molecular targets, with inlubition being approached by use of 'naked' or payload-carrying monoclonal antibodies (MAbs), genomically selected small molecules and other strategies such as gene therapy, antisense and RNA inhibition (RNAi). In addition to the selection of target-specific agents, patients are also being selected for therapy by clinical genomic, proteomic and other 'theranostic' methods. 1IIe Advantage of Antibodies The success of agents such as Rituxan® (Biogen Idec/Genentech; rituximab), Herceptin® (Genentech/ Roche; trastuzumab) and Avastin® (Genentech/Roche; bevacizumab), has underscored the utility of MAbbased therapeutics. Specific molecular targeting is central to the function of antibodies, and this innate ability can be harnessed to target tumor cells. Because of their specificity, MAbs are viewed as safer than chemotherapy; they do not interact with other drugs and their longer half-life offers a dosing advantage. MAbs can be engineered to kill cells directly or to induce cell death by harnessing the immune system. They can also be used to sensitize cells to chemotherapy.
Patient selection can be key to success Antibodies also offer the increased ability to select patients likely to respond to therapy by testing for the presence of the targeted antigen in the tumor. The case of Herceptin, which targets the plasma membrane-associated receptor HER2 (overexpressed in some breast cancers), illustrates the criticality of therapy-associated diagnostics. According to Hal Barron, if trials had been performed without preselecting HER2-positive breast cancer patients, 2200 patients would have been required to show a benefit of therapy in 10% of the patients, rather than the 50% response rate exhibited in the targeted population.
Targeting the epidermal growth factor receptor (EFGR), a molecular relative of HER2, Erbitux® (1m Clone Systems/Bristol-Myers Squibb; cetuximab) was recently approved in conjunction with an immunohistochemical EGFR test kit (EGFR pharmDx TIl ; DakoCytomation) to select eligible patients with metastatic colorectal cancer. But will diagnostics help all targeted therapies? Other agents targeting EFGR have had mixed results with regard to selection of a specific patient population for therapy. In addition to MAbs such as Erbitux and ABX-EGF (Abgenix/ Amgen; panitumumab), EGFR inhibition is also being approached using targeted small molecules to control the growth of a variety of solid tumors. The effects of EGFR have been attributed to the activation of multiple diverse intracellular signaling pathways, and this may result in a relatively broad patient population.
Response to the small-molecule EGFR inhibitor Iressa® (AstraZeneca; gefitinib) has been shown to be significantly influenced by activating mutations in the
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