Navigation Links
Hundreds of alterations and potential drug targets to starve cancer tumors identified
Date:4/21/2013

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

"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 changessuch as an increase in nucleotide biosynthesis and glycolysisappear 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 leukemia, mutations in this enzyme are known to produce a specific metabolite2-hydroxyglutaratethat 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 enzymessuccinate dehydrogenase and fumarate hydratasecan 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 isoenzymesuitable for fast cell proliferationwas 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."


'/>"/>

Contact: Karin Eskenazi
ket2116@cumc.columbia.edu
212-342-0508
Columbia University Medical Center
Source:Eurekalert

Related medicine news :

1. Hundreds of random mutations in leukemia linked to aging, not cancer
2. Physicians at Pain Care Bring Hope to Hundreds of Pain Management Patients Who Previously Had None Through Use of a New Procedure Called Spinal Cord Stimulation
3. High-throughput sequencing shows potentially hundreds of gene mutations related to autism
4. Medtronic Infuse Bone Graft Lawsuits: Bernstein Liebhard LLP Notes New Report Predicting Hundreds of Medtronic Infuse Lawsuits
5. Molecular subtypes and genetic alterations may determine response to lung cancer therapy
6. Vanderbilt study finds diverse genetic alterations in triple-negative breast cancers
7. Study identifies potential treatment for lethal childhood leukemia
8. McMaster researchers find potential for new uses of old drug
9. Army researcher develops potential vaccine carrier
10. UNC study shows potential to revive abandoned cancer drug by nanoparticle drug delivery
11. New study of NIH funding allocations suggests potential efficiency gains
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/27/2016)... ... June 27, 2016 , ... "FCPX editors can now reveal their ... Cut Pro X," said Christina Austin - CEO of Pixel Film Studios. , ... Pro X users can now reveal the media of their split screens with ...
(Date:6/27/2016)... Overland Park, KS (PRWEB) , ... June 27, 2016 , ... ... leader in retailers of Eyeglasses . , Millions of individuals in the United ... life, eyeglasses have become a way to both correct vision and make a fashion ...
(Date:6/26/2016)... North Carolina (PRWEB) , ... June 26, 2016 , ... ... release of a new product that was developed to enhance the health of felines. ... for centuries. , The two main herbs in the PawPaws Cat Kidney Support ...
(Date:6/25/2016)... Austin, TX (PRWEB) , ... June 25, 2016 , ... ... Fellow of the American College of Mohs Surgery and to Dr. Russell Peckham for ... popular and highly effective treatment for skin cancer. The selective fellowship in Mohs Micrographic ...
(Date:6/25/2016)... Long Beach, CA (PRWEB) , ... June 25, 2016 , ... ... from UCLA with Magna Cum Laude and his M.D from the David Geffen School ... San Diego and returned to Los Angeles to complete his fellowship in hematology/oncology at ...
Breaking Medicine News(10 mins):
(Date:6/26/2016)... Story Highlights: ... the health care industry is causing providers to review ... Deloitte offers a suite of solutions for health care ... cost optimization: labor resource analysis, revenue cycle optimization and ... outcomes and better economics ...
(Date:6/24/2016)... June 24, 2016 ... announced the addition of the " Global Markets ... This report focuses ... an updated review, including its applications in various applications. ... market, which includes three main industries: pharmaceutical and biotechnology, ...
(Date:6/24/2016)... -- Research and Markets has announced the addition ... report to their offering. ... The World Market for Companion Diagnostics covers the world ... in the report includes the following: , ... by Region (N. America, EU, ROW), 2015-2020 , World ...
Breaking Medicine Technology: