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Old 05-02-2013, 02:06 AM
gdpawel gdpawel is offline
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Default Sweeping Study Of Cancer Metabolism Identifies Hundreds Of Alterations And Potential

A massive study analyzing gene expression data from 22 tumor types has identified multiple metabolic expression changes associated with cancer. The analysis, conducted by researchers at Columbia University Medical Center, also identified hundreds of potential drug targets that could cut off a tumor's fuel supply or interfere with its ability to synthesize essential building blocks. The study was published in the online edition of Nature Biotechnology.

The results should ramp up research into drugs that interfere with cancer metabolism, a field that dominated cancer research in the early 20th century and has recently undergone a renaissance.

"The importance of this new study is its scope," said Dennis Vitkup, PhD, associate professor of biomedical informatics (in the Initiative in Systems Biology) at CUMC, the study's lead investigator. "So far, people have focused mainly on a few genes involved in major metabolic processes. Our study provides a comprehensive, global view of diverse metabolic alterations at the level of gene expression."

Cell metabolism is a dynamic network of reactions inside cells that process nutrients, such as glucose, to obtain energy and synthesize building blocks needed to produce new cellular components. To support uncontrolled proliferation, cancer needs to significantly reprogram and "supercharge" a cell's normal metabolic pathways.

The first researcher to notice cancer's special metabolism was German biochemist Otto Warburg, who in 1924 observed that cancer cells had a peculiar way of utilizing glucose to make energy for the cell. "Although a list of biochemical pathways in normal cells was comprehensively mapped during the last century," said Dr. Vitkup. "We still lack a complete understanding of their usage, regulation, and reprogramming in cancer."

"Right now we have something like a static road map. We know where the streets are, but we don't know how traffic flows through the streets and intersections," said Jie Hu, PhD, a postdoctoral researcher at Columbia and first author of the study. "What researchers need is something similar to Google Traffic, which shows the flow and dynamic changes in car traffic."

Drs. Hu and Vitkup's study is an important step toward achieving this dynamic view of cancer metabolism. Notably, the researchers found that the tumor-induced expression changes are significantly different across diverse tumors. Although some metabolic changes - such as an increase in nucleotide biosynthesis and glycolysis - appear to be more frequent across tumors, others, such as changes in oxidation phosphorylation, are heterogeneous.

"Our study clearly demonstrates that there are no single and universal changes in cancer metabolism," said Matthew Vander Heiden, MD, PhD, assistant professor at MIT, and a co-author of the paper. "That means that to understand transformation in cancer metabolism, researchers will need to consider how different tumor types adapt their metabolism to meet their specific needs."

The researchers also found that expression changes can mimic or cooperate with cancer mutations to drive tumor formation. A notable example is the enzyme isocitrate dehydrogenase. In several cancers, such as glioblastoma and acute myeloid leukemiaterm, mutations in this enzyme are known to produce a specific metabolite - 2-hydroxyglutarate - that promotes tumor growth. The Columbia team found that isocitrate dehydrogenase expression significantly increases in tumors with the recurrent mutations. Such an overexpression may create an efficient enzymatic factory for overproduction of 2-hydroxyglutarate.

The analysis also led the researchers to an interesting finding in colon cancer. In several other cancers, mutations in two enzymes - succinate dehydrogenase and fumarate hydratase - can promote tumor formation as a result of efflux from mitochondria and accumulation of their substrates, fumarate and succinate. The researchers found that in colon cancer, accumulation of these metabolites may be caused by a significant decrease in the enzymes' expression. This was confirmed when metabolomics data from colon tumor patients showed significantly higher concentrations of fumarate in tumors than in normal tissue.

"These are just several examples of how cancer cells use various creative mechanisms to hijack the metabolism of native cells for their own purposes," said Dr. Vitkup.

For cancer researchers looking for new drug targets, Dr. Vitkup's team also found hundreds of differences between normal and cancer cells' use of isoenzymes. This opens up additional possibilities for turning off cancer's fuel and supply lines. Isoenzymes often catalyze the same reactions, but have different kinetic properties: Some act quickly and sustain rapid growth, while others are more sluggish. In kidney and liver cancers, for example, a quick-acting aldolase isoenzyme - suitable for fast cell proliferation - was found to be more prevalent than the more typical slow-moving version found in normal kidney and liver tissue. Although a few examples of differential isoenzyme expression in tumors were already known, the Columbia researchers identified hundreds of isoenzymes with cancer-specific expression patterns.

"Inhibiting specific isoenzymes in tumors may be a way to selectively hit cancer cells without affecting normal cells, which could get by with other isoenzymes," said Dr. Hu.

In fact, a recent study from Matthew Vander Heiden's laboratory demonstrated the potential of targeting a specific isoenzyme, pyruvate kinase M2, expression of which often increases in tumors. "The comprehensive expression analysis suggests that a similar approach could potentially be applied in multiple other cases," said Dr. Vander Heiden.

Targeting metabolism may be a way to strike cancer at its roots. "Cancer cells usually have multiple ways to turn on their growth program," said Dr. Vitkup. "You can knock out one, but the cells will usually find another pathway to turn on proliferation. Targeting metabolism may be more powerful, because if you starve a cell of energy or materials, it has nowhere to go."

References:

Fuel Lines of Tumors Are New Target: [url]http://nyti.ms/10QMkY1

The paper is titled, "Heterogeneity of tumor-induced gene expression changes in the human metabolic network." The other authors are Jason W. Locasale (Cornell University), Jason H. Bielas (Fred Hutchinson Cancer Research Center, Seattle, Wash.; and University of Washington, Seattle, Wash.), Jacintha O'Sullivan (St. Vincent's University Hospital, Dublin, Ireland), Kieran Sheahan St. Vincent's University Hospital, Dublin, Ireland), and Lewis C. Cantley (Harvard Medical School).

Dr. Vander Heiden is a consultant and advisory board member, and Dr. Cantley is a consultant and founder, of Agios Pharmaceuticals. The authors report no other financial or potential conflicts of interest.

This work was supported by National Institutes of Health grant GM079759 to Dr. Vitkup and National Centers for Biomedical Computing grant U54CA121852 to Columbia University. Dr. Locasale is supported by an NIH Pathway to Independence Award R00CA168997. Dr. Bielas is supported by an Ellison Medical Foundation New Scholar award AG-NS-0577-09, a National Institute of Environmental Health Sciences grant R01ES019319, and New Development Funds from the Fred Hutchinson Cancer Research Center. Dr. Vander Heiden acknowledges support from the Burroughs Wellcome Fund, the Damon Runyon Cancer Research Foundation, the Smith Family, and the National Cancer Institute.

Columbia University Medical Center. "Sweeping Study Of Cancer Metabolism Identifies Hundreds Of Alterations And Potential Drug Targets To Starve Tumors." Medical News Today. MediLexicon, Intl., 23 Apr. 2013.

For Personalizing Cancer Therapy, Metabolic Profiles Are Essential [url]http://cancerfocus.org/forum/showthread.php?t=3615

Thomas Seyfried: Cancer: A Metabolic Disease With Metabolic Solutions

[url]https://www.youtube.com/watch?v=SEE-oU8_NSU&feature=youtu.be
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Last edited by gdpawel : 05-29-2015 at 02:27 PM. Reason: Additional info
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Old 05-03-2013, 08:32 AM
gdpawel gdpawel is offline
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Default The Effectiveness of Metabolomic Analysis

According to Dr. Robert A. Nagourney of Rational Therapeutics, cancer therapists have long sought mechanisms to match patients to available therapies. Current fashion revolves around DNA mutations, gene copy and rearrangements to select drugs. While every cancer patient may be as unique as their fingerprints, all of the fingerprints on file with the federal automated fingerprint identification system database doesn't add up to a hill of genes (pun intended), if you can't connect them to the criminal.

According to J. Michael Bishop of the University of California, San Francisco, cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy. The issue is whether that is sufficient. They argue that it isn't because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome. Metabolic profiling will be essential for defining each cancer and choosing the best treatment accordingly, researchers say.

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor. The altered metabolism of tumors has been considered a target for anticancer therapy.

According to laboratory oncologists, much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell's metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time.

Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase the rate of success. One of them is the need to redouble the efforts in the study of basic metabolism and the growing field of metabolomics (the metabolome).
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Old 05-11-2013, 11:18 AM
gdpawel gdpawel is offline
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Default Metabolomics

Metabolomics is a newly emerging field of "omics" research concerned with the comprehensive characterization of the small molecule metabolites in biological systems. It can provide an overview of the metabolic status and global biochemical events associated with a cellular or biological system.

An increasing focus in metabolomics research is now evident in academia, industry and government, with more than 500 papers a year being published on this subject. Indeed, metabolomics is now part of the vision of the NIH road map initiative (E. Zerhouni (2003) Science 302, 63-64&72).

Many other government bodies are also supporting metabolomics activities internationally. Studying the metabolome (along with other "omes") will highlight changes in networks and pathways and provide insights into physiological and pathological states.

The concept of Systems Biology and the prospect of integrating transcriptomics, proteomics, and metabolomics data is exciting and the integration of these fields continues to evolve at a rapid pace. Developments in informatics, flux analysis and biochemical modeling are adding new dimensions to the field of metabolomics.

To be able to walk from genetic or environmental perturbations to a phenotype to a specific biochemical event is exciting. Metabolomics has the promise to enable detection of disease states and their progression, monitor response to therapy, stratify patients based on biochemical profiles, and highlight targets for drug design.

The metabolomics field builds on a wealth of biochemical information that was established over many years.

The Metabolomics Society

Systems biology utilizes a combination of biochemistry, proteomics, genomics, metabolomics and bioinformatics to better understand the contribution of each element of the system to the whole.

Systems Biology Is The Future Of Medical Research

[url]http://cancerfocus.org/forum/showthread.php?t=3473
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