American journal of pharmacogenomics : genomics-related research in drug development and clinical practice最新文献

Pharmacogenomics is defined as research into inherited genetic variations that determine an individual's response to therapeutic agents. In oncology, pharmacogenomics based on somatic molecular alterations inherited by subsequent cancer cell generations forms the basis of molecular targeting of novel therapeutic agents. What has emerged from clinical experience with such agents is the need for appropriate pharmacodiagnostic approaches to ensure the drugs are correctly targeted. Given the broad range of pharmacogenomic agents currently under evaluation for cancer therapy, it appears that a rapid extension of pharmacodiagnostic profiling will be required in the next 5-10 years, if not sooner. If this is to be successfully achieved, lessons learned in the past, particularly during the development of HER2 (ERBB2) testing for directing trastuzumab therapy in breast cancer, may provide a valuable framework for the development of future pharmacodiagnostic assays system. This article reviews the biological and clinical rationale for targeting breast cancer with trastuzumab and the steps taken to validate and improve pharmacodiagnostic procedures for testing tumor HER2 protein expression and HER2 gene amplification. Attention is given to quality assurance and reproducibility of testing approaches and the optimal selection of patients for response to trastuzumab. This approach serves as a paradigm for the future development of pharmacodiagnostic tests in oncology.

The concept of personalized medicine--that medical care can be tailored to the genomic and molecular profile of the individual--has repercussions that extend far beyond the technology that makes it possible. The adoption of personalized medicine will require changes in healthcare infrastructure, diagnostics and therapeutics business models, reimbursement policy from government and private payers, and a different approach to regulatory oversight. Personalized medicine will shift medical practices upstream from the reactive treatment of disease, to proactive healthcare management including screening, early treatment, and prevention, and will alter the roles of both physician and patient. It will create a greater reliance on electronic medical records and decision support systems in an industry that has a long history of resistance to information technology. Personalized medicine requires a systems approach to implementation. But in a healthcare economy that is highly decentralized and market driven, it is incumbent upon the stakeholders themselves to advocate for a consistent set of policies and legislation that pave the way for the adoption of personalized medicine. To address this need, the Personalized Medicine Coalition (PMC) was formed as a nonprofit umbrella organization of pharmaceutical, biotechnology, diagnostic, and information technology companies, healthcare providers and payers, patient advocacy groups, industry policy organizations, major academic institutions, and government agencies. The PMC provides a structure for achieving consensus positions among these stakeholders on crucial public policy issues, a role which will be vital to translating personalized medicine into widespread clinical practice. In this article, we outline the goals of the PMC, and the strategies it will take to foster communication, debate, and consensus on issues such as genetic discrimination, the reimbursement structures for pharmacogenomic drugs and diagnostics, regulation, physician training and medical school curricula, and public education.

This is the second part of a four-part review on potential therapeutic targeting of oncogenes. The previous part introduced the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes, which we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part I included a discussion of growth factors and tyrosine kinases. This portion of the review covers intermediate signaling molecules and the various strategies used to inhibit their expression or decrease their activities.

This is the third paper in a four-part serial review on potential therapeutic targeting of oncogenes. The previous parts described the involvement of oncogenes in different aspects of cancer growth and development, and considered the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes that we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part one discussed growth factors and tyrosine kinases and part two discussed intermediate signaling molecules. This portion of the review covers transcription factors and the various strategies being used to inhibit their expression or decrease their activities.

Genomic-based methodologies are increasingly used at all stages of drug development. The most extensive applications have occurred in early drug discovery stages due to advances in technologies that allow for automated synthesis and characterization of organic compounds, and for high-throughput screening of these molecules against known drug targets. The adaptation of genomic-based methodologies in later stages of drug development presents a more difficult task. In this review we describe how genomics can be used to identify previously uncharacterized pharmacologic actions that provide a basis for the development of new classes of antimycotic agents or for adverse event aversion. Clinically, novel antimycotics are gravely needed. This review provides a perspective on new technologies that will bridge the gap between drug discovery and development that may enable more rapid access to new antimycotic agents.

This is the final part of a four-part serial review on oncogenes and their potential use as targets for cancer therapy. Previous sections discussed various categories of oncogenes (growth factors, tyrosine kinases, intermediate signaling molecules, and transcription factors) and the advances made in various strategies being used to alter their actions. This part describes four oncogenes, MDM2, BCL2, XIAP, and Survivin, that are involved in regulation of the cell cycle and apoptosis.

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy.

The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The biological variability among patient samples as well as the huge dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we focus here on cancer classification using mass spectrometry (MS) for proteomic profiling and biomarker identification. Recent advances in MS technology are starting to enable high-throughput profiling of the protein content of complex samples. For cancer classification, the protein samples from cancer patients and noncancer patients or from different cancer stages are analyzed through MS instruments and the MS patterns are used to build a diagnostic classifier. To illustrate the importance of feature selection in cancer classification, we present a method based on support vector machine-recursive feature elimination (SVM-RFE), demonstrated on two cancer datasets from ovarian and lung cancer.

Acquired resistance to imatinib mesylate is an increasing and continued challenge in the treatment of BCR-ABL tyrosine kinase positive leukemias as well as gastrointestinal stromal tumors. Stable isotope-based dynamic metabolic profiling (SIDMAP) studies conducted in parallel with the development and clinical testing of imatinib revealed that this targeted drug is most effective in controlling glucose transport, direct glucose oxidation for RNA ribose synthesis in the pentose cycle, as well as de novo long-chain fatty acid synthesis. Thus imatinib deprives transformed cells of the key substrate of macromolecule synthesis, malignant cell proliferation, and growth. Tracer-based magnetic resonance spectroscopy studies revealed a restitution of mitochondrial glucose metabolism and an increased energy state by reversing the Warburg effect, consistent with a subsequent decrease in anaerobic glycolysis. Recent in vitro SIDMAP studies that involved myeloid cells isolated from patients who developed resistance against imatinib indicated that non-oxidative ribose synthesis from glucose and decreased mitochondrial glucose oxidation are reliable metabolic signatures of drug resistance and disease progression. There is also evidence that imatinib-resistant cells utilize alternate substrates for macromolecule synthesis to overcome limited glucose transport controlled by imatinib. The main clinical implications involve early detection of imatinib resistance and the identification of new metabolic enzyme targets with the potential of overcoming drug resistance downstream of the various genetic and BCR-ABL-expression derived mechanisms. Metabolic profiling is an essential tool used to predict, clinically detect, and treat targeted drug resistance. This need arises from the fact that targeted drugs are narrowly conceived against genes and proteins but the metabolic network is inherently complex and flexible to activate alternative macromolecule synthesis pathways that targeted drugs fail to control.