The path to personalized medicine

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The path to personalized medicine

Joanne M. Meyer and Geoffrey S. Ginsburg

Current Opinion in Chemical Biology 2002, 6:434-438

Advances in personalized medicine, or the use of an individual's molecular profile to direct the practice of medicine, have been greatly enabled through human genome research. This research is leading to the identification of a range of molecular markers for predisposition testing, disease screening and prognostic assessment, as well as markers used to predict and monitor drug response. Successful personalized medicine research programs will not only require strategies for developing and validating biomarkers, but also coordinating these efforts with drug discovery and clinical development.

Introduction

The realization of personalized medicine, or the fine tailoring of the practice of medicine to an individual, is being fostered through numerous efforts aimed at characterizing individual differences in molecular processes underlying disease pathogenesis, disease progression and the response to therapeutics. Once these molecular differences are understood, therapeutic development will be enhanced by using the information to identify individuals more likely to benefit from a given intervention strategy. High-throughput genomic technologies are already providing the data that will serve as the foundation of personalized medicine. Here, we briefly describe the current state of those technologies and highlight the directions required to fully develop and integrate personalized medicine into practice. We draw upon a range of examples that demonstrate the relevance of molecular markers throughout the development and treatment of disease, including markers for disease predisposition, screening and progression, as well as markers for drug response and drug monitoring ( Fig. 1).

Individual differences in the development of disease and response to therapeutics

Clearly, for many common diseases, there is abundant evidence to suggest that the molecular underpinnings of disease susceptibility, and its natural history, differ markedly among individuals. For example, while it has been demonstrated in numerous investigations that the development of obesity, asthma, type 2 diabetes and cardiovascular disease are under genetic control [1–4] , there is no evidence to suggest that the genetic basis is due to variation in just a single gene. Instead, the consensus has emerged that subtle genetic differences in one or many of several genes serve as risk factors for these illnesses. Thus, while genetic variants in the melanocortin-4 receptor may explain some risk for developing obesity [5], and polymorphisms in PPAR-gamma may correlate with the risk of developing type 2 diabetes [6•], these variants do not explain all of these genetic diseases. There are certainly more genetic variants, or predisposition markers, to uncover. In the context of personalized medicine, the ultimate goal of these types of studies is to provide a suite of markers that can be used to assess one's lifetime risk of developing disease in the presence of various environmental (e.g. diet, lifestyle) variables.

As with disease predisposition, individual differences characterize disease progression. For example, some individuals with impaired glucose tolerance will proceed quite rapidly to type 2 diabetes, whereas others proceed slowly. Similarly, individuals diagnosed with rheumatoid arthritis may or may not develop erosive disease. In both of these cases, genetic variation, that is, variation measured at the DNA level, may be a good predictor of the individual differences that emerge as disease progresses. For example, Brinkman et al. [7] have demonstrated that a polymorphism in TNF-

correlates with erosive rheumatoid arthritis, but shows no association with non-erosive disease. Alternatively, variation in disease progression may be best predicted by a combination of genetic and environmental factors, the impact of which is indexed through changes in gene expression in relevant tissues, or changes in secreted protein levels in serum or synovial fluid. In our laboratories, we are using a range of genomics technologies to find markers for disease progression that are both stable (DNA) as well as dynamic (mRNA, protein), giving us the opportunity to evaluate the utility of both types of markers in prospective studies.

Given that individual variability in disease predisposition and progression exists and has the potential of being molecularly characterized, it is not at all surprising that such differences also characterize response to therapeutics (see Fig. 1). Marked individual variation in the efficacy and toxicity of therapeutic compounds is common and can have a profound impact on the success of a pharmaceutical clinical development program. Clearly, molecular markers that predict the variation in these endpoints could be extremely useful in clinical trials, drug development and clinical practice, as they would allow the identification of patients who would benefit most from the drug.

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17th - 30th July 2002

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The path to personalized medicine