Lung Cancer Cells' Survival Gene Seen as Drug Target

One of the deadliest forms of cancer appears to carry a specific weakness.

When a key gene called 14-3-3zeta is silenced, lung cancer cells can't survive on their own, researchers have found.

The gene is a potential target for selective anti-cancer drugs, says Haian Fu, professor of pharmacology, hematology & oncology at Emory University School of Medicine and Emory Winship Cancer Institute.

The research results will be published the week of Dec. 24 in the Proceedings of the National Academy of Sciences (PNAS). The paper's first author is Zenggang Li, PhD, a postdoctoral fellow in Dr. Fu's laboratory.

Lung cancer kills more Americans annually than any other type of malignancy, according to the National Cancer Institute. Yet treatment options are very limited, Dr. Fu says.

"The recent trend towards targeted therapies requires us to understand the altered signaling pathways in the cell that allow cancer to develop," he says. "If you think about genes that are dysregulated in cancer as drivers or passengers, we want to find the drivers and then, aim for these drivers during drug discovery."

Fu and his collaborator, Fadlo Khuri, MD, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumors. In addition, recent research elsewhere shows that survival of lung cancer patients is worse if the gene is on overdrive in their tumors, Dr. Fu says.

14-3-3 genes are found in mammals, plants and fungi. In the human body, they come in seven flavors, each given a Greek letter. Scientists describe the proteins they encode as adaptors that clamp onto other proteins. The clamping function depends on whether the target protein is phosphorylated, a chemical switch that regulates processes such as cell division, growth, or death.

"We knew that 14-3-3 is important in controlling EGFR (epidermal growth factor receptor) signaling, which is a main pathway driving lung cancer," Fu says. A couple of recently introduced drugs that were shown to be effective against lung cancer target EGFR, he adds.

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Studies Identify DNA Regions Linked to Nicotine Dependence

Americans are bombarded with antismoking messages, yet at least 65 million continue to light up. Genetic factors play an important role in this continuing addiction to cigarettes, suggest scientists at Washington University School of Medicine in St. Louis.

In two studies in the January 2007 issue of Human Molecular Genetics, the scientists show that certain genetic variations can influence smoking behaviors and contribute to a person's risk for nicotine dependence.

The smoking-related genes identified normally facilitate communication between nerve cells in the brain. One gene in particular, the alpha-5 nicotinic cholinergic receptor (CHRNA5) gene, was a very strong indicator of risk for nicotine dependence. Individuals with a specific variation in the gene seemed to have a two-fold increase of developing nicotine dependence once exposed to cigarette smoking. CHRNA5 is from a class of receptors that plays a role in dopamine pathways in the brain, which are linked to a person's experience of pleasure.

The researchers also identified genes related to gamma aminobutyric acid (GABA) receptors, another set of proteins vital to nerve cell function. Both GABA and nicotinic receptors had been suspected of involvement in nicotine addiction, but these findings strengthen those suspicions.

The studies also identified a gene not previously known to be involved with nicotine dependence. Called the Neurexin 1 (NRXN1) gene, it helps regulate the balance between excitatory mechanisms — those that increase communication between nerve cells — and inhibitory mechanisms — those that slow firing between nerve cells.

"An imbalance between excitatory and inhibitory activity in the brain may predispose people to addiction, such as alcoholism, drug dependence or nicotine dependence," says Laura Jean Bierut, M.D., associate professor of psychiatry and principal investigator of both studies. "The Neurexin gene we've identified is really a key factor in the balance between inhibition and excitatory activity in neurons."

Bierut suspects a large number of genes are involved in nicotine dependence, and she says understanding how they work may make it possible to develop new treatments for smoking cessation.

The research team analyzed data from almost 2,000 participants in two ongoing studies. One, called the Collaborative Genetic Study of Nicotine Dependence, is a U.S.-based sample that includes both addicted smokers and "social" smokers from St. Louis, Minneapolis and Detroit. The other is an Australian study of smokers of European ancestry called the Nicotine Addiction Genetics study.

The scientists combined two approaches for analyzing genetic information. One approach scanned the entire human genome for suspicious areas of DNA while the second approach closely examined specific target genes.

"The combination of these two approaches represents the most powerful and extensive study on nicotine dependence to date and is an important step in a large-scale, genetic examination of nicotine dependence," says Elias A. Zerhouni, M.D., the director of the National Institutes of Health, which funded the studies. "As more genomic variations are discovered that are associated with substance abuse, we can better understand addictive disorders."

The researchers identified an area of DNA variation that seems to alter the function of a nicotinic receptor protein. That small variation makes a big difference in risk for nicotine dependence.

Current drug treatments for nicotine dependence continue to be only marginally successful, and Bierut believes using information about genetic traits to tailor medications to individuals could make them significantly more effective. "The type of variant you have at this particular receptor — the alpha-5 nicotinic receptor — may actually predict whether or not you will do well on nicotine replacement therapy," she says.

<---Anyone who's been or is a smoker, knows how hard it is to quit cigarettes. Even after we hear again and agian the risk of lung cancer for some reason we pick up a cigarette, ignoring the cancer statistics. Smokefree seems far away. But eventually, there is a point when quitting smoking makes the most sense.The effect of smoking takes too much of a toll.--->

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Climate Change Regulation Coming As Business Gets Into the Act

U.S. government regulation on the emissions blamed for climate change may be only a matter of time as industry further gets on the climate change bandwagon.

A Democrat, or Sen. John McCain, a Republican who has moved to deal with climate change issues, may well be president once a new occupant is sworn into the White House. Such a move bolsters chances of further federal regulation of carbon emissions, according to David Sandalow, environment scholar at The Brookings Institution in Washington.

"So one way to think about this is if we have either a Democrat or John McCain as president starting in 2009, we will have a president ready to sign legislation on this issue and I think the odds in Vegas on either a Democrat or John McCain being president are not bad, and I think this is happening," says Sandalow, previously assistant secretary for oceans, environment, and science at the U.S. State Department and senior director for environmental affairs at the National Security Council.

Carbon emissions from the burning of fossil fuels is thought to be affecting Earth's climate in an increasingly severe way.

Controlling emissions and dealing with climate change is increasingly becoming a public policy issue. U.S. industry once resisted carbon regulation but a growing number of companies are addressing climate change.

Sandalow cites industrial titan General Electric and retail giant Wal-Mart as two examples of firms taking on climate change.

"General Electric, which I believe is the largest company in the world in terms of market capitalization, has announced major initiatives in this area," Sandalow says. "Jeffrey Immelt, the CEO, sees his company making lots of money by the move toward clean energy over the course of the next several decades."

Wal-Mart is taking very aggressive steps to save energy and cut costs, he adds.

"As a result of doing that, they have had Al Gore down in Arkansas to talk to all of the Wal-Mart employees around the country," Sandalow says. "So I think this is happening and I believe federal legislation is coming, a lot of the business community knows this, and the only question is how and when."

Former vice president Gore has long been a champion of dealing with climate change and recently raised the profile of climate change further with his documentary film, An Inconvenient Truth.

Meanwhile, Caterpillar Inc. (NYSE: CAT) Chairman and CEO Jim Owens joined a diverse group of businesses and environmental organizations to call on U.S. policymakers to establish a mandatory emissions reduction program to address climate change. Along with Caterpillar, members of the alliance -- known as the U.S. Climate Action Partnership (USCAP) -- include market leaders Alcoa, BP America, Duke Energy, DuPont, General Electric, PG&E, PNM Resources and four leading non-governmental organizations - Environmental Defense, Natural Resources Defense Council, Pew Center on Global Climate Change and World Resources Institute.

At a news conference Monday at the National Press Club in Washington, USCAP released a set of principles and recommendations as the basis to develop a market-driven policy framework on climate change.

"Caterpillar believes in the need for a market-based approach to the aggressive development of current and future clean technologies that reduce emissions and sustain the environment," Owens says. "As a global manufacturer, we're committed to being part of the process of finding policy solutions that meet the needs of our customers, including those currently involved in energy production. Achieving energy independence for our country will require innovation that leads to new energy sources but also new technologies to improve the use of existing abundant resources such as coal."

With 2005 sales and revenues of $36.34 billion, Caterpillar is the world's leading manufacturer of construction and mining equipment, diesel and natural gas engines and industrial gas turbines.

"Clean coal, clean diesel and combined heat and power applications are just a few examples of critical technologies that must be a part of any climate change policy. These technologies, coupled with incentives for the development of new, breakthrough approaches will yield increased sustainability and economic opportunity," Owens adds.

Caterpillar supports a U. S. federal-level approach that is well integrated into a harmonized global system of greenhouse gas reduction initiatives, in particular one that avoids local or regional development of separate paths -- requiring separate technology -- in achieving emissions targets. Proposed solutions also must factor in the broad economic impact as well as the impact on existing energy sectors.

"Reducing greenhouse gas emissions can -- and should -- provide more economic opportunities than risks for industry and the economy," says Owens. "The goals of reduced emissions and economic growth are not mutually exclusive. As the world's largest maker of construction and mining equipment and a technology leader, one of the reasons that Caterpillar is pleased to have a seat at this table is to focus on market-based solutions to issues that impact manufacturers and key customer groups, especially coal."


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Researchers 1st To Map Gene That Regulates Adult Stem Cell Growth

A new discovery in stem cell research may mean big things for cancer patients in the future. Gary Van Zant, Ph.D., and a research team at the University of Kentucky published their findings in Nature Genetics, an international scientific journal.

The researchers genetically mapped a stem cell gene and its protein product, Laxetin, and building on that effort, carried the investigation all the way through to the identification of the gene itself. This is the first time such a complete study on a stem cell gene has been carried out. This particular gene is important because it helps regulate the number of adult stem cells in the body, particularly in bone marrow. Now that it has been identified, researchers hope the gene, along with its protein product Latexin, can be used clinically, such as for ramping up the stem cell count in cancer patients undergoing chemotherapy and bone marrow transplantation.

The researchers agreed that this very process is not only interesting, but important because of its usefulness in a wide variety of future genetics studies.

"We're thinking about cancer in a big way," Van Zant says. "This is a great example of translational research – from the most basic type of genetic research all the way to possible treatments for patients."

One big obstacle chemotherapy patients face is stem cell loss after treatments. This limits the dosage amount and types of chemotherapy that can be given. But if Latexin were used to increase the stem cell count, patients would be able to receive increased doses of chemotherapy and be able to recover more quickly. Increased stem cell counts also would be valuable during bone marrow transplants, where the greatest number of stem cells are desired to help a patient recover from cancer.

Another possible use for Latexin would be to help increase the number of stem cells available in umbilical cord blood, which also is used to transplant healthy stem cells in blood marrow transplants. Currently, stem cell transplants with cord blood can only be used in children because cord blood does not contain enough stem cells for an amount needed to be transplanted into an adult.

The only stem cell population that has been examined for effects of Latexin to date is in bone marrow. Van Zant says it is possible, even probable, that other stem cell populations in tissues such as the liver, skin, pancreas or brain may be similarly affected by Latexin. This could open up new therapeutic strategies such as using stem cells for the treatment of other diseases and conditions such as liver disease, diabetes and central nervous system damage as a result of trauma or stroke.

The researchers also are looking into the possible role the gene plays in transforming healthy stem cells into cancerous ones, such as in leukemia and lymphomas. If the gene does in fact play such a role, it is possible that it also could provide the keys to new therapies.

Van Zant describes his discovery as an elation. He worked on the project for six years with Ying Liang, a former graduate student who is now a postdoctoral fellow at UK. Van Zant says this research and publication of the journal article is the culmination of a difficult but rewarding scientific journey.

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Newsweek: Genome Sequencing Begins To Payoff

Three years after scientists announced they had sequenced the human genome, new knowledge about how our genesaffect our health is transforming the way diseases are understood, diagnosed, treated-and even predicted, reports Newsweek senior writer Claudia Kalbin.

Newsweek's latest installment of its ongoing "Health for Life" series,"What's Next in Medicine" is in the December 11 issue, on newsstands Monday, December 4.

Today gene tests are available for more than 1,300 diseases, including cystic fibrosis and hemophilia. And now, as genetic screening gets cheaper and faster, researchers are hunting down the biological underpinnings of more-complex disorders that involve multiple genes-big,rampaging illnesses that strike millions of Americans every year. On the list: type 2 diabetes, Alzheimer's, heart disease and depression.

If the scientists are right, genetic tests for some of these diseases could beavailable by 2010. "We are on the leading edge of a genuine revolution,"says Dr. Francis Collins, head of the National Human Genome Research Institute.

The gene tests currently offered for certain diseases, like breast andcolon cancer, affect only a small percentage of total cases. But the impacton a single life can be huge. The key: being able to do something to ward off disease. "Genetic testing offers us profound insight," says Dr. Stephen Gruber, of the University of Michigan. "But it has to be balanced with ourability to care for these patients."

For example, the risk of breast and ovarian cancers in people with BRCA mutations can be reduced by frequent screening and radical surgery. Having healthy breasts or ovaries removed isn't easy, but the payoff--an end to constant anxiety and a pre-emptivestrike at disease--can be well worth it.

"Most women I've met who've had prophylactic surgery are glad they made the choice even if they're unhappy they were put in that position," says Sue Friedman, a breast-cancer survivor and head of FORCE, an advocacy and support group focused on hereditary cancers. "It's a double- edged sword."

The value of testing becomes especially murky -- and ethically complicated -- when there is no way to prevent or treat disease, as in the case of early-onset Alzheimer's, which often strikes before the age of 50,or Huntington's, Kalb reports.

Today, only about 5 percent of people whoare at risk for Huntington's, a devastating neurological disorder, take the test. Many are worried that genetic testing will put their health insurance or job security in jeopardy. Some people, however, can't live with uncertainty.

Stephanie Vogt knew Huntington's ran in her family -- her paternal grandfather and his three brothers all died from complications ofthe disease-and she wanted to find out where she stood. "As soon as I foundout there was a test, I just had to do it," she says.

In August 2000, after comprehensive genetic counseling, Stephanie, her sister, Victoria and their mother, Gayle Smith, learned her results: positive. "It was like a scene out of the Matrix, where everything freezes and starts again," says Stephanie.

On good days Stephanie feels empowered; on bad days she's frightened. "But most of the time," she says, "I'm comfortable with the fact that I have the knowledge."

Testing is just one piece of the genomic revolution. A major goal is to create new sophisticated therapies that home in on a disease's biological glitch, then fix the problem. Already, genes are helping to predict a patient's response to existing medications. A prime example in this field of pharmacogenetics, says Dr. Wylie Burke of the University of Washington, is a variant of the gene called TPMT, which can lead to life-threatening reactions to certain doses of chemotherapy. Knowing a patient's genotype,or genetic profile, may also help researchers uncover new preventative therapies for intractable diseases.

At Johns Hopkins University School of Medicine, Dr. Christopher Ross has tested several compounds shown to slow the progression of Huntington's in mice. Now he wants to test them in people who are positive for the Huntington's mutation but have not yetdeveloped symptoms--a novel approach to clinical drug trials, which almost always involve sick people seeking cures. "We're using genetics to move from treating the disease after it happens," he says, "to preventing the worst symptoms of the disease before it happens."