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Kaddurah-Daouk R.,Duke University | Weinshilboum R.M.,Molecular Therapeutics | Weinshilboum R.M.,Center for Individualized Medicine
Clinical Pharmacology and Therapeutics | Year: 2014

Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.

Klee E.W.,Mayo Medical School | Rohrer Vitek C.R.,Center for Individualized Medicine | Schultz C.,Center for Individualized Medicine at Mayo Clinic | Wieben E.D.,Medical Genome Facility at Mayo | Farrugia G.,Center for Individualized Medicine at Mayo Clinic
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2014

There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes. © 2014 Wiley Periodicals, Inc.

Kaddurah-Daouk R.,Duke University | Weinshilboum R.,Molecular Therapeutics | Weinshilboum R.,Center for Individualized Medicine
Clinical Pharmacology and Therapeutics | Year: 2015

The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and Systems Pharmacology (QSP). This new research direction might significantly advance the discovery, development, and clinical use of therapeutic drugs. Research communities from computational biology, systems biology, and biological engineering - working collaboratively with pharmacologists, geneticists, biochemists, and analytical chemists - are creating and modeling large data on drug effects that is transforming our understanding of how these drugs work at a network level. In this review, we highlight developments in a new and rapidly growing field - pharmacometabolomics - in which large biochemical data-capturing effects of genome, gut microbiome, and environment exposures is revealing information about metabotypes and treatment outcomes, and creating metabolic signatures as new potential biomarkers. Pharmacometabolomics informs and complements pharmacogenomics and together they provide building blocks for QSP. © 2015 American Society for Clinical Pharmacology and Therapeutics.

CHICAGO (Reuters) - Just as 23andMe has made peace with the U.S. Food and Drug Administration, another direct-to-consumer genetics company is testing the regulatory waters with the launch of a $249 DNA test designed to predict drug response. The test, from tiny startup DNA4Life based in Mandeville, Louisiana, comes in the wake of 23andMe's two-year tussle with the FDA over its direct-to-consumer personal DNA testing service, which the FDA ordered off the market in 2013. Last month, 23andMe relaunched its service with a limited number of genetic tests for carrier screening - tests that show whether an individual carries genes associated with 36 different disorders that could be passed on to a child. But the agency has yet to approve direct-to-consumer tests for pharmacogenetics, a field experts believe could be much riskier in the hands of consumers, who might use the information to make decisions about the drugs they are taking. Richard Zimmer, chief executive of DNA4Life, said he has been watching developments at the FDA closely and said his regulatory advisers believe the test does not need FDA approval. Zimmer said tests such as his are regulated as lab-developed tests under guidelines established by the Clinical Laboratory Improvement Amendments or CLIA, which do not require companies to prove clinical validity or usefulness in aiding patient care. In response to a query by Reuters, FDA spokesman Eric Pahon said the agency "actively regulates genetic tests sold directly to consumers, including pharmacogenetics tests, to make sure they are safe and do what they claim to do." "Without FDA oversight, the safety and efficacy of the tests have not been determined and could potentially lead to patient harm," Pahon said. When told of FDA's stance, Zimmer said, "We would be delighted to have a conversation with the FDA," but added that it is not under the agency's purview. "Of course, the government can do what it likes." Currently, pharmacogenetics tests are ordered directly by a treating physician and are not available to consumers. One, GeneSight, made by Assurex Health, is covered by Medicare and some insurers. GeneSight's sticker price is more than $3,000, but the company says the average patient pays no more than $330. To get DNA4Life's $249 test and report, consumers must agree to share their results with their doctor and answer a few screening questions. A network of DNA4Life doctors uses those answers to determine whether to order the test, which assesses 12 common genes affecting drug metabolism and response. It is a setup similar to one used by Pathway Genomics, which in September launched a DNA cancer screening test for healthy people. They, too, offered online screening tests and physician ordering. Just a few weeks after the launch, FDA sent Pathway a warning letter expressing concern that test could harm public health. For Zimmer, the push is personal, born out of the experiences of his 16-year-old daughter, who suffered with severe depression while her doctor tried to find the right medication and dose to treat her. Zimmer believes consumers should have access to their own data through an affordable test. Dr. Keith Stewart of Mayo Clinic's Center for Individualized Medicine said there are no direct-to-consumer pharmacogenetic tests and "at this point, FDA approval is likely to be required." Stewart said studies showing the tests are clinically valuable are "few and far between," and those that have been done have been sponsored by the testing companies. The problem, said pharmacogenetics expert Dr. Josh Peterson of Vanderbilt University, is that patients, and even doctors, struggle to understand what to do with the results. "I think that is one of the FDA's concerns," he said. "I'm an internist. That would be one of my concerns as well."

Kang N.,University of Minnesota | Shah V.H.,Center for Individualized Medicine | Urrutia R.,Center for Individualized Medicine | Urrutia R.,GI Research Unit
Molecular Cancer Research | Year: 2015

Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment (TME), are a key source of the extracellular matrix (ECM) that constitutes the desmoplastic stroma. Through remodeling of the reactive tumor stroma and paracrine actions, CAFs regulate cancer initiation, progression, and metastasis, as well as tumor resistance to therapies. The CAFs found in stroma-rich primary hepatocellular carcinomas (HCC) and liver metastases of primary cancers of other organs predominantly originate from hepatic stellate cells (HSTC), which are pericytes associated with hepatic sinusoids. During tumor invasion, HSTCs transdifferentiate into myofibroblasts in response to paracrine signals emanating from either tumor cells or a heterogeneous cell population within the hepatic tumor microenvironment. Mechanistically, HSTC-tomyofibroblast transdifferentiation, also known as, HSTC activation, requires cell surface receptor activation, intracellular signal transduction, gene transcription, and epigenetic signals, which combined ultimately modulate distinct gene expression profiles that give rise to and maintain a new phenotype. The current review defines a paradigmthat explains how HSTCs are activated into CAFs to promote liver metastasis. Furthermore, a focus on the most relevant intracellular signaling networks and epigenetic mechanisms that control HSTC activation is provided. Finally, we discuss the feasibility of targeting CAF/activated HSTCs, in isolation or in conjunction with targeting cancer cells, which constitutes a promising and viable therapeutic approach for the treatment of primary stroma-rich liver cancers and liver metastasis. © 2014 American Association for Cancer Research.

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