This article is part of a multi-part CME-certified activity titled Translational Therapeutics at the Platelet Vascular Interface. In order to achieve all of the activity’s learning objectives, please read all of the components of the activity listed in the Table of Contents and follow the “Instructions for Participation and Obtaining CME Credit” outlined prior to the Introduction.
The past 15 years have witnessed a revolution in drug discovery, fueled by investment in high throughput screening, bioinformatics, genomics, and combinatorial chemistry. However, despite an increasing abundance of “validated” drug targets, the number of drugs approved by the US Food and Drug Administration (FDA) reaching the market has stalled. A similar revolution in the process of drug development1 could alleviate this problem but is hindered by a critical dearth of the relevant human capital—individuals who can take proof-of-concept studies using quantitative assays of drug action in cells and model systems and project them across the translational divide to perform detailed studies of drug response in humans. Ideally, these mechanistic studies in humans would guide the selection of dose on a “personalized” basis. Although the number of individuals who command expertise in the relevant skill sets to pursue such research has dwindled in academia, industry, and the regulatory agencies, fewer still of this cadre are equipped to apply “unbiased” technologies further to refine studies of drug action and safety in humans.
Nascent interdisciplinary training programs are increasingly emphasizing the importance of translational research in academic institutions in the United States, Europe, and elsewhere.2,3 However, this new science needs a label—a brand—if it is to aggregate resources and attract outstanding physicians and scientists to such an arduous career path. “Translational Medicine and Therapeutics” captures some critical elements of this endeavor: the integration of basic and clinical pharmacology; modern quantitative approaches to imaging and the assessment of unbiased and biased biomarkers of drug response; genomics; and computational biology. “Systems pharmacology” paradigms are being developed to understand the breadth of drug response in cells, model systems, organs, and ultimately humans.4
These proceedings are derived from a satellite meeting held in conjunction with the annual scientific meeting of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology of the American Heart Association, held in Chicago in April 2007. It is entitled “Translational Therapeutics at the Platelet-Vascular Interface” and was designed to highlight how information on basic mechanisms derived from cells and model systems might be integrated with present understanding of drug action in humans.
The focus of this meeting on the platelet-vascular interface affords an appropriate context in which to consider the opportunities for this new, interdisciplinary science. Cardiovascular disease remains the leading cause of death in the United States and is a rapidly emerging cause of death in the developing world. Despite our understanding of many aspects of thrombogenesis and vascular function, our therapeutic repertoire to tackle problems at this interface is remarkably limited. Challenges include the spontaneous plaque fracture of atherosclerotic lesions and consequent thrombosis; the refinement of quantitative and global proteomic platforms that may elucidate further the mechanisms of plaque destabilization; platelet activation and interactions between these and other blood cells at the vascular interface; and the integration of more comprehensive genomic information with kinetic and dynamic aspects of drug response to segregate increasing drug efficacy from safety in humans.
The articles in this supplement highlight both the challenges and the opportunities for scientists with interdisciplinary training in this area. Zimmerman and Weyrich describe a novel paradigm—signal-dependent translation—in which proteins are translated rapidly in platelets from constitutive or posttranscriptionally processed mRNA in response to conventional ligand-dependent signals to platelet activation. Desmond Fitzgerald complements this work by describing his discovery of novel secreted platelet proteins using proteomics platforms.5 Brass describes the application of new approaches to in vivo imaging of thrombogenesis to characterize novel platelet and vascular proteins and to segregate previously unrecognized roles for conventional platelet signaling pathways in mice. Freedman describes the complex roles of oxidant stress at the platelet-vascular interface and how it might modulate the effect of mediators that both augment and restrain platelet interactions with the vessel wall. May builds on this theme, expanding beyond the platelet as merely a mediator of thrombosis to consider its critical contribution to the inflammatory response, integrating the interactions between monocytes, circulating progenitor cells, and the vessel wall in the initiation of atherogenesis. Moving across the translational divide, Liao, Michelson, and Patrono highlight emerging information and gaps in our knowledge concerning drugs with established efficacy in the treatment of atherothrombotic disease. Liao describes the impact of dipyridamole on both cyclic guanosine monophosphate (GMP) and adenosine monophosphate (AMP) in platelets and the vessel wall, with particular emphasis on modulation of nitric oxide activity. Michelson highlights how the more uniform pharmacokinetic profile attained by prasugrel likely contributes to more antithrombotic efficacy but also more risk of serious bleeds when compared with the older P2Y12 antagonist clopidogrel. Finally, Patrono and Rocca consider aspirin. Despite its established efficacy in the secondary prevention of cardiovascular disease and stroke, many questions remain—the segregation of benefit from risk in primary prevention; its place, if any, in the chemoprevention of cancer; and how its dose-dependent, differential impact on cyclooxygenase (COX)-1 and COX-2 might be most usefully exploited in the treatment of patients with both arthritis and cardiovascular disease.
The pause in drug development is likely to be temporary, particularly with the diversification of therapeutic platforms and the development of modes of targeted delivery. However, realization of our translational opportunities is presently constrained by respect for disciplinary boundaries that have become outmoded.
We need to educate synthesizers, so that they can become the analyzers.
“James Joyce was a synthesizer, trying to bring in as much as he could. I am an analyzer, trying to leave out as much as I can.”
Sources of Funding
Dr FitzGerald is the McNeill Professor of Translational Medicine and Therapeutics. His work is supported by grants RR023567, HL81012, HL083799, HL54500, and HL-053558 from the National Institutes of Health.
During the past year Dr FitzGerald has consulted for AstraZeneca, Daiichi, Merck, Nicox, Novartis, and Wyeth and received grant support for investigator-initiated research from Boehringer Ingelheim, Merck, and Bayer.
Burroughs Wellcome Fund. Programs & grant guidelines: translational research. http://www.bwfund.org/programs/translational/clinical_scientists_main.html. Accessed January 2, 2008.
Wellcome Trust. Interdisciplinary training programmes for clinicians in translational medicine and therapeutics. http://www.wellcome.ac.uk/node2165.html. Accessed January 2, 2008.