Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Hundreds of Alterations and Potential Drug Targets to Starve Tumors Identified

Published: Monday, April 22, 2013
Last Updated: Monday, April 22, 2013
Bookmark and Share
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 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.

“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 leukemia, 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.”

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.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Neurodevelopmental Syndrome Identified
Study pinpoints underlying genetic mutations, raising hopes for targeted therapies.
Friday, April 22, 2016
New Link Between Obesity and Diabetes Found
Targeting a single enzyme that raises both sugar and insulin levels in the obese could prevent and treat diabetes.
Monday, November 25, 2013
Is There a Role for Vitamins in Cancer Prevention?
According to recent national surveys, approximately 40 percent of U.S. adults take multivitamins/multiminerals.
Monday, August 12, 2013
Study Reveals Genes That Drive Brain Cancer
About 15 percent of glioblastoma patients could receive personalized treatment with drugs currently used in other cancers.
Tuesday, August 06, 2013
Key Molecular Pathways Leading to Alzheimer’s Identified
Research approach highlights potential therapeutic targets.
Thursday, July 25, 2013
New Genetic Cause of Pulmonary Hypertension Identified
Study finds druggable target for rare fatal lung disease.
Thursday, July 25, 2013
Mutation Linked to Congenital Urinary Tract Defects
Findings point to new diagnostic category.
Thursday, July 18, 2013
Mouse Study Suggests Lead May Trigger Schizophrenia
Behavioral and MRI study in mice points to a synergistic relationship between lead exposure and schizophrenia gene.
Monday, June 10, 2013
Many Birth Defects in Heart Caused by Spontaneous Mutations
A study has found that at least 10 percent of cases stem from genetic mutations that occur spontaneously early in development.
Thursday, May 30, 2013
Common Childhood Asthma Not Rooted in Allergens, Inflammation
Discovery of origins of a unique form of asthma may lead to a precision medicine approach to treatment.
Friday, May 24, 2013
Looking for the Telltale Gene
A new genetic test allows parents to peer into their unborn children's medical future.
Friday, May 24, 2013
New Gene Associated with Almost Doubled Alzheimer’s Risk in African-Americans
ABCA7, a minor gene variant in whites, is major player in African-Americans.
Wednesday, April 10, 2013
Schizophrenia Gene Networks Found, and a Link to Autism
Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify.
Thursday, November 15, 2012
New de novo Genetic Mutations in Schizophrenia Identified
Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease.
Thursday, October 04, 2012
New de novo Genetic Mutations in Schizophrenia Identified
Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease.
Thursday, October 04, 2012
Scientific News
Monovar Drills Down Into Cancer Genome
Rice, MD Anderson develop program to ID mutations in single cancer cells.
Autism and Cancer Share a Remarkable Number of Risk Genes
Researchers with the UC Davis Comprehensive Cancer Center, MIND Institute identify more than 40 common genes.
Number Of Known Genetic Risk Factors For Endometrial Cancer Doubled
An international collaboration of researchers has identified five new gene regions that increase a woman’s risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine.
Genetic Variant May Help Explain Why Labradors Are Prone To Obesity
A genetic variation associated with obesity and appetite in Labrador retrievers – the UK and US’s favourite dog breed – has been identified by scientists at the University of Cambridge. The finding may explain why Labrador retrievers are more likely to become obese than dogs of other breeds.
How Scientists Use DNA to Track Disease Outbreaks
They’re the top questions on everyone’s mind when a new disease outbreak happens: where did the virus come from? When did this happen? How long has it been spreading in a particular country or group of people?
Genetic Risk Factors of Disparate Diseases Share Similar Biological Underpinnings
Penn Institute for Biomedical Informatics and colleagues identify "roadmap" of disease mechanisms to identify candidate drug targets.
Stem Cells Know How to Unwind
Research led by the Babraham Institute with collaborators in the UK, Canada and Japan has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells.
Childhood Asthma Research Receives $2M
Research into the impact of a child’s upbringing and social and physical environments on the development of asthma will receive $2 million to tackle the condition that affects as many as one in three Canadians.
Five New Breast Cancer Genes Found
Discovery of mutations paves the way for personalised treatment of breast cancer.
Cell Transplant Treats Parkinson’s in Mice
A University of Wisconsin—Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!