Anti-cancer clinical drug development is currently costly and slow with a high attrition rate. There is thus an
urgent and unmet need to integrate pharmacodynamic biomarkers into early phase clinical trials in the framework provided
by the “pharmacologic audit trail” in order to overcome this challenge. This review discusses the rationale, advantages
and disadvantages, as well as the practical considerations of various tissue-based approaches to perform pharmacodynamic
studies in early phase oncology clinical trials using case histories of molecular targeting agents such as PI3K,
m-TOR, HSP90, HDAC and PARP inhibitors. These approaches include the use of normal “surrogate” tissues such as peripheral
blood mononuclear cells, platelet-rich plasma, plucked hair follicles, skin biopsies, plasma-based endocrine assays,
proteomics, metabolomics and circulating endothelial cells. In addition, the review discusses the use of neoplastic
tissues including tumor biopsies, circulating tumor DNA and tumor cells and metabolomic approaches. The utilization of
these tissues and technology platforms to study biomarkers will help accelerate the development of molecularly targeted
agents for the treatment of cancer.
Keywords: Clinical trials, molecular targeted agents, oncology, pharmacodynamic biomarkers, PI3K, PARP inhibitors, neoplastic, genomic hybridization and microarray, pharmacological audit trail, surrogate tissues.
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