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Educational Session: Registration Strategies in Cancer Drug Development: Opportunities and Challenges

The critical role of molecular biomarkers in clinical trials of novel cancer therapeutics.

The Inst. of Cancer Research, Sutton, United Kingdom

Abstract

The progressive elucidation of the molecular basis of cancer is yielding unprecedented opportunities for development of new therapeutic agents. At the same time, the need to translate our knowledge of molecular causation into patient benefit as quickly as possible creates many challenges. In particular there is an urgent need for academia and the pharmaceutical industry to work closely together to ensure that clinical trials are carried out both rapidly and intelligently. The careful design and conduct of drug registration studies is exceptionally important. Selecting clinical endpoints for pivotal registration studies is clearly a key issue. As part of the construction of global strategies for drug registration, the role of genomics and molecular biomarkers is playing an increasingly important role. This presentation will focus on the discovery and development of molecular biomarkers of drug action and response. The experimental approaches taken involve: 1) candidate markers and pathways analysed by western blotting/ELISA; 2) gene expression microarray analysis; 3) proteomic investigations; and 4) metabolomic profiling using magnetic resonance spectroscopy. Using these approaches, biomarkers have been identified for use in preclinical and clinical development of drugs designed to inhibit molecular targets including cyclin-dependent kinases, PI3 kinase, Hsp90 molecular chaperone, histone deacetylases amongst others. The availability of pharmacokinetic (PK) and pharmacodynamic (PD) endpoints is absolutely critical for rational drug development in the modern era. These assays allow us to understand: 1) now much drug reaches the general circulation and ideally the molecular target in the tumour cell; and 2) the effect that the drug has on the molecular target, the cognate biochemical pathway and downstream biological effects. The creative use of PK and PD endpoints, coupled to the analysis of the status and expression of the molecular target, allows us to construct a so-called "pharmacologic audit trail" that captures information on all of the successive events from drug administration, through molecular and cellular changes, all the way to biological (e.g. proliferation, apoptosis, angiogenesis, invasion, etc) and clinical outcomes (therapeutic response and toxicity). In this way, the interconnections between stages in the audit trail can be monitored and interpreted. In turn this provides a rational basis for informed decision-making, including proof of concept, go/no go and the selection of optimal dose and schedule. Methodological refinements continue, with minimally invasive molecular and functional imaging endpoints showing considerable potential. Coupled to novel, robust, validated and informative endpoints, the audit trail concept can contribute in a major way to registration strategies and in particular towards the development of personalized therapies targeted to the genomic make-up of the individual patient.