Abstract
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.
Highlights
Oncology drug development is exploiting the rapidly evolving advances in our understanding of the biology of cancer by targeting the molecular pathological aberrations which drive progression of individual neoplasms [1]
Phase I oncology clinical trials are conducted to recommend a Phase II dose and schedule by defining toxicity and evaluating the pharmacokinetic / pharmacodynamic profiles. While none of these parameters can be used in isolation, we argue that the incorporation of specific pharmacodynamic endpoints allows drug development to proceed rationally, allowing the examination of pre-specified scientificallyevaluable variables and testing of specific hypotheses [7]
The use of normal “surrogate” tissues for biomarker studies in Phase I trials offer distinct advantages, including (a) low incurred procedural risks, (b) amenability to repeated sampling, allowing the temporal characterization of pharmacodynamic effects, (c) the possibility to predict target modulation in tumor tissue based on pharmacokineticpharmacodynamic modeling and extrapolation from animal models, and (d) facilitation of phamacogenomic studies using germ line DNA
Summary
Oncology drug development is exploiting the rapidly evolving advances in our understanding of the biology of cancer by targeting the molecular pathological aberrations which drive progression of individual neoplasms [1]. The use of normal “surrogate” tissues for biomarker studies in Phase I trials offer distinct advantages, including (a) low incurred procedural risks, (b) amenability to repeated sampling, allowing the temporal characterization of pharmacodynamic effects, (c) the possibility to predict target modulation in tumor tissue based on pharmacokineticpharmacodynamic modeling and extrapolation from animal models (an example being the use of PBMCs in the development of everolimus, discussed below [19, 20]), and (d) facilitation of phamacogenomic studies using germ line DNA. Studies involving 31P-NMR have been published demonstrating a reproducible and robust metabolic signature of altered phospholipid metabolism with the application of 17-AAG, a potent HSP90 inhibitor, to colon cancer-bearing xenograft models [80]
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