Target-driven drug and diagnostic development: Lessons from HER2

PL02-03

An increasing number of targeted therapies for cancer have reached the market or entered development in the past decade. Many of these treatments target molecular defects present only within a subset of a particular type of histologically-identifiable cancer. The need to identify such sub-populations creates complexities for both development and commercialization of new targeted agents. Genentech's successful development of Herceptin, a HER2-targeted humanized monoclonal antibody, can be viewed as an early and instructive example of the challenges facing the field.
 Early work in the 1980's by Dennis Slamon and his collaborators demonstrated that significant genomic amplification of the HER2 locus was present in approximately 20% of ductal carcinomas of the breast. Genomic amplification was shown to be associated with overexpression of the HER2 oncoprotein on the surface of tumor cells and breast cancer cell lines. Overexpression was also shown to be required for anti-proliferative responses to anti-HER2 antibodies. Herceptin was therefore developed specifically for tumors in which HER2 is overexpressed and clinical development included only such patients. The implications of this strategy will be discussed, focusing on the need for high-quality, reliable, accessible diagnostics during development and commercialization of targeted anti-cancer agents. Broader implications of targeted treatment approaches for the rational pathologic classification of cancers will also be considered. An update on the diagnostic approaches being taken to support the development of newer treatments directed at HER pathways will be presented.