Study Finds Treatment With New Drug Might Make Tumor Cells More Sensitive to Therapy

Scientists at St. Jude Children's Research Hospital have shown that it might be possible to
make tumor cells more sensitive to irradiation and some types of chemotherapy by treating them with a drug that cripples their ability to repair DNA damage caused by these therapies.

The St. Jude researchers demonstrated in the laboratory that a molecule called CP466722 rapidly blocks the ATM protein's ability to orchestrate a series of biochemical events that culminate in the repair of DNA damaged by irradiation. The molecule exerted its effect in small quantities, and its effects rapidly ended after it was removed from cells, suggesting that such
a treatment in humans would not have significant or long-term side effects, the researchers say.

Results of the study were published in the Sept. 15 issue of the journal Cancer Research.

ATM plays a critical role in repairing a type of DNA damage called double-strand breaks, in which each of the two strands making up this molecule are cut, according to Dr. Michael Kastan, M.D., director of the St. Jude Comprehensive Cancer Center. This process protects cells from the potentially lethal or mutation-causing effects of free oxygen radicals and irradiation--both of which routinely threaten them, he added. Kastan is senior author of the report on these findings.
Children lacking the gene for ATM develop ataxia-teleangiectasia, a disease that causes several debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation that leads to irreparable, double-stranded DNA breaks.

"We found that inhibition of ATM activity with CP466722 produces cellular effects that are identical to those seen in cells that lack ATM," Kastan says. "It's as if we temporarily turned normal cells into cells indistinguishable from those of children with ataxia-teleangiectasia."

The protective role of ATM makes it a tempting target for researchers looking for a way to prevent cancer cells from repairing DNA damage caused by therapeutic irradiation, Kastan notes.

Previously Kastan's team found how ATM is activated by a signal from damaged DNA only seconds after the damage occurs. The activated ATM, in turn, activates other proteins by attaching a molecule called phosphate to them in a process called phosphorylation. This sets off a cascade of biochemical reactions that amplifies the initial ATM response leading to
repair of the double-stranded break.

"Our ability to rapidly and reversibly regulate ATM activity with CP466722 also gives us a new tool to study the function of this protein, which plays such a critical role in the ability of both normal and cancerous cells to repair their DNA," says Michael Rainey, a postdoctoral fellow in the St. Jude Department of Oncology. "This approach will help us learn more about the repair events triggered by ATM in response to DNA damage." Rainey is the report's first author.

Kastan also says that CP466722 provides his team with a basic chemical structure that they can build upon as they try to modify the molecule to enhance its potency and specificity and move studies from isolated cells to mouse models.

"Results of those mouse model studies would help us to determine if and how to proceed with studies in patients with cancer," Kastan says.

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Scientists Create DNA Tubes With Programmable Sizes for Nanoscale Manufacturing

Scientists at the California Institute of Technology (Caltech) have developed a simple process for mass producing molecular tubes of identical--and precisely programmable--circumferences. The technological feat may allow the use of the molecular tubes in a number of nanotechnology applications.

The molecular tubes are composed of wound-up strands of DNA. DNA has been considered an ideal construction material for self-assembling molecular structures and devices because two complementary DNA strands can automatically recognize and bind with each other. DNA has been used to form rigid building blocks, known as tiles, and these tiles can further assemble into extended lattice structures, including tubes. However, it has been difficult to control the diameters of such tubes.

Peng Yin, a senior postdoctoral scholar in bioengineering and computer science at Caltech's Center for Biological Circuit Design, along with his colleagues has designed a series of flexible, single-stranded DNA molecules, called single-stranded DNA tiles. Each single-stranded tile is exactly 42 bases long and contains four modular binding sites. By pairing up the complementary binding sites, these single-stranded tiles bind with each other in a particular orientation like Lego pieces snapped together, forming a tube composed of parallel DNA helices.

The circumference of the resulting tube is determined by the number of different 42-base pieces used in its construction. For example, four pieces create a tube with a circumference of 12 billionths of a meter (or 12 nanometers); five pieces, a 15-nanometer-circumference tube; and six pieces, an 18-nanometer tube.

"We are not the first to make DNA tubes with controlled circumferences. However, compared with previous approaches, our method is distinctively simple and modular," says Yin. The simplicity and modularity of their approach permits the description of the tube design using a simple graphical abstraction system developed earlier this year in the laboratory of Niles Pierce, associate professor_of applied and computational mathematics and bioengineering at Caltech.

Just as a variety of wood sizes are used in construction projects--two by four inches for framing walls, two by eight inches for roof rafters, or four by four inches for fence posts--having nanotubes of various, precisely controlled sizes provides their user with more options. In addition, nanotubes of different sizes have varying mechanical properties; for example, tubes with a smaller diameter are more flexible and tubes with a larger diameter are more rigid. The nanotubes might eventually serve as templates for manufacturing nanowires with controlled diameters; the diameters of electron-conducting nanowires would help determine the electronic properties of the devices they are used to construct.

"The simplicity of the single-stranded tile approach promises to enable us to design ever more complex self-assembling molecular systems. The work is simultaneously elegant and useful," says Erik Winfree, associate professor of computer science, computation and neural systems, and bioengineering at Caltech. Winfree's laboratory was the primary host of Yin's research at Caltech.

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New Method Offers Insight into Radiation Damage to DNA

A new technique for assessing the damage radiation causes to DNA indicates that the spatial arrangement of damaged sites, or lesions, is more important than the number of lesions in determining the severity of the damage. The technique, developed by scientists at the U.S. Department of Energy (DOE)'s Brookhaven National Laboratory, helps reveal why high-energy charged particles such as the heavy ions in outer space are more potentially harmful than
lower-energy forms of radiation such as x-rays and gamma rays.

The research could help clarify the risks faced by future astronauts flying long-term missions to the moon or Mars. It was published online on March 19, in the journal Nucleic Acids Research.

The technique uses different colored fluorescent "tags" instead of radioactive ones to monitor repair of damage to DNA, life's genetic instruction molecule. Because these fluorescent tags reduce the amount of hazardous waste associated with the research (and its cost) the Brookhaven scientists, Betsy Sutherland and Brigitte Paap, now at Arizona State University, have been recognized by DOE's Office of Science for their "Best in Class" pollution prevention innovation.

"Understanding the effects on humans of radiation exposure - whether in the natural environment, in outer space, in the workplace, or due to radiation therapy - requires insight into the induction and repair of damage to DNA," says Sutherland, an expert in the study of space radiation. "It's very rewarding to come up with a new technique that helps us understand this process while at the same time reducing the waste associated with traditional techniques."

Radiation can damage the DNA "double helix" -- a two-stranded, twisting molecule -- in a variety of ways: 1) by knocking off one or more of the DNA "bases" known by the letters A, T, G, and C, which form the bonds between the two strands of the double helix; 2) by oxidizing these bases; or 3) by breaking through one or both strands. All can result in a failure of the molecule to perform its main task - telling cells which proteins to make. That can lead to out-of-control
cell growth (cancer) or death.

Cells can often repair radiation-damaged DNA, using specialized enzymes to excise and patch up the damaged segments. But damage from ionizing particle radiation appears to be harder to repair than that caused by lower-energy forms of radiation such as x-rays and gamma rays.

Scientists have long hypothesized that the reason for this difference was that the high-energy ionizing particles caused more complex damage containing many lesions close together on the DNA, leading to slower and less-accurate repair. The technique developed by Sutherland and Paap allowed them to test this hypothesis.

Using standard techniques of molecular biology, the scientists created synthetic DNA with known lesions in a variety of spatial arrangements with a red fluorescent tag attached to one end of the strand and a green fluorescent tag at the other end. They then applied a DNA repair enzyme, which clips the DNA at damaged sites. The scientists then used gel electrophoresis to separate the fragments according to their length. By looking at the red- and green-tagged
bands, and determining their length, the scientists were able to measure how well the repair enzyme recognized and repaired the DNA damage.

The results were surprising: Instead of being dependent on the number of lesions, the ability of the repair enzyme to recognize the damaged sites appeared to be most affected by the spatial arrangement of lesions on the DNA strands.

The scientists found that the enzyme readily recognized and repaired lesions on one of the DNA's two strands that occurred all to one side of a reference lesion on the opposite strand (think of it as "upstream"). These upstream lesions were successfully repaired regardless of whether there were only two or many lesions in the damage.

If the lesions occurred "downstream" from the reference lesion, however, the repair enzyme was unable to work properly, no matter whether the clustered damage was a simple, two-lesion cluster, similar to those caused by x-rays, or a complex multi-lesion cluster like those induced by space radiation. When the lesions occurred in a two-sided cluster both up and downstream from the reference lesion, again the repair enzyme worked poorly.

"Since x-rays produce about half upstream, easily repaired clusters and about half downstream, repair-resistant clusters, about half of them would be readily repaired," Sutherland says. "The heavy, charged particles in space radiation, on the other hand, produce much more complex, two-sided clusters, containing so many lesions that most of them are repair-resistant. This directional dependence of the ability to repair lesions explains why damage from charged-particle radiation, such as that encountered in outer space, is more harmful," she says.

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Advance in DNA Sequencing Announced

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Researchers Find Monkeys Able to Fend Off AIDS-like Symptoms With Enhanced HIV Vaccine

Researchers at the University of Pennsylvania School of Medicine have discovered that using an immune system gene to enhance a vaccine used to study HIV in macaque monkeys provides the animals with greater protection against simian HIV (SHIV) than an unmodified vaccine. This multi-year study found that the addition of a molecule called Interleukin-15 effectively boosts the effects of a vaccine derived from the DNA of simian HIV. The study illustrates that DNA vaccine effectiveness can be improved by the inclusion of specific immune adjuvants, or helpers.

The findings are published in last week’s online edition of the Proceedings of the National Academy of Sciences.

“DNA vaccine technology has great promise for the development of vaccines and immune therapeutics for a variety of infectious diseases and cancers,” says senior author David Weiner, professor of Pathology and Laboratory Medicine at Penn. While previous studies have established that the technology can induce immune responses safely, “improving the immune potency of this platform is critical for further development in humans.”

The research builds on previous work aimed at engineering a more potent immune response to SHIV DNA vaccine technology. Mouse model studies previously showed that the cytokine IL-15 -- a substance that can improve the body's natural response to infection and disease -- helps better immune responses and protection, while this study mirrors those findings in a larger, non-human primate species.

In this study, the group of macaques that was injected with the vaccine containing a loop of DNA enabling them to make IL-15 developed no signs of AIDS-like symptoms when exposed to live SHIV, compared to four animals in the control group that received only the DNA vaccine. The modified vaccine appeared to help suppress viral replication among the IL-15 group.

Next, Weiner’s team will study the protected macaques to determine the actual mechanism of their protection, and seek out any pockets of the virus that may be hiding in specific immune compartments. The approach will also be tested for safety and immunogenicity in humans through the HIV Vaccine Trials Network.

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Study Identifies Gene Alterations in Lung Cancer

An international team of scientists, supported in part by the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), has announced that its systematic effort to map the genomic changes underlying lung cancer has uncovered a critical gene alteration not previously linked to any form of cancer. The research, published in the advance online issue of the journal Nature, also revealed more than 50 genomic regions that are frequently gained or lost in lung adenocarcinoma, the most common type of lung cancer in the United States.

“This view of the lung cancer genome is unprecedented, both in its breadth and depth,” says senior author Matthew Meyerson, a senior associate member of the Broad Institute of MIT and Harvard in Cambridge, Mass., and an associate professor at Dana-Farber Cancer Institute and Harvard Medical School in Boston. “It lays an essential foundation, and has already pinpointed an important gene that controls the growth of lung cells. This information offers crucial inroads to the biology of lung cancer and will help shape new strategies for cancer diagnosis and therapy.”

Each year more than 1 million people worldwide die of lung cancer, including more than 150,000 in the United States. The new study focused on lung adenocarcinoma, which, according to the National Cancer Institute (NCI), is the most frequently diagnosed form of lung cancer in the United States, accounting for approximately 30 percent of cases.

New approaches to cancer treatment rely on a deeper understanding of what goes wrong in tumor cells to spur uncontrolled growth. Through decades of research, it has become clear that lung cancer -- like most human cancers -- stems mainly from DNA changes that accrue in cells throughout a person’s life. But the nature of these changes and their biological consequences remain largely unknown, which has inspired the recent formation of multi-disciplinary teams that are using new genomic tools and technologies to study cancer in a more systematic, comprehensive manner.

The latest study was conducted as part of the Tumor Sequencing Project (TSP), an ongoing effort to apply large-scale approaches to the identification of genomic changes in lung adenocarcinoma. NHGRI is a major funder of TSP, which unites scientists and clinicians throughout the cancer research community.

“This outstanding work clearly demonstrates the value of comprehensive approaches for exploring the genomic underpinnings of cancer. The impacts of these findings extend far beyond lung cancer and indicate that many more important cancer-related genes still await our discovery,” NHGRI Director Francis Collins says. “Now, we must forge ahead and apply this strategy as quickly as possible to other common types of cancer.”

Specifically, the TSP researchers uncovered a total of 57 genomic changes that occur frequently in lung cancer patients. Of these changes, more than 40 appear to be associated with genes not previously known to be involved in lung adenocarcinoma. More research is needed to precisely identify and characterize these genes, but researchers are excited by the possibility that their findings may suggest new ways of attacking this deadly cancer.

The most common abnormality identified by the TSP team involves a region on chromosome 14 that encompasses two known genes, neither of which had been previously associated with cancer. Through additional studies in cancer cells, the researchers discovered that one of the genes, NKX2.1, influences cancer cell growth. NKX2.1 normally acts as a master regulator that controls the activity of other key genes in cells lining the lungs’ tiny air sacs, called alveoli. The discovery that a gene functioning in a select group of cells - rather than in all cells - can promote cancer growth may have broad implications for the design of drugs for a wide range of cancers.

“The genomic landscape of lung cancer gives us a systematic picture of this terrible disease, confirming things we know, but also pointing us to many missing pieces of the puzzle. More broadly, the study represents a general approach that can and should be used to analyze all types of cancer,” says Eric Lander, one of the study’s co-authors and founding director of the Broad Institute of MIT and Harvard.

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Critical Protein Prevents DNA Damage From Persisting Through Generations

A protein long known to be involved in protecting cells from genetic damage has been found to play an even more important role in protecting the cell's offspring. New research by a team of scientists at Rockefeller University, Howard Hughes Medical Institute and the National Cancer Institute shows that the protein, known as ATM, is not only vital for helping repair double-stranded breaks in DNA of immune cells, but is also part of a system that prevents genetic damage from being passed on when the cells divide.

Early in the life of B lymphocytes -- the immune cells responsible for hunting down foreign invaders and labeling them for destruction -- they rearrange their DNA to create various surface receptors that can accurately identify different intruders, a process called V(D)J recombination. Now, in an study published online in the journal Cell, Rockefeller University Professor Michel Nussenzweig, in collaboration with his brother André Nussenzweig at NCI and their colleagues, shows that when the ATM protein is absent, chromosomal breaks created during V(D)J recombination go unrepaired, and checkpoints that normally prevent the damaged cell from replicating are lost.

Normal lymphocytes contain a number of restorative proteins, whose job it is to identify chromosomal damage and repair it or, if the damage is irreparable, prevent the cell from multiplying. Earlier research by André and Michel Nussenzweig, who is an investigator at HHMI, had identified other DNA repair proteins that are important during different phases of a B lymphocyte's life. It was during one of these studies, which examined genetic damage late in the life of a B cell, that they came across chromosomal breaks that could not be explained.

So the researchers began to look into the potential role of V(D)J recombination. "We were not expecting it to be responsible for the breaks we were seeing," says Michel, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology. "Because for it to be responsible, the breaks would have had to happen early on, the cell would have to divide, mature, maintain the breaks, and stay alive with broken chromosomes."
This, in fact, was precisely what they found.

The ATM protein appears to have two roles in a B cell: It helps repair the DNA double-strand breaks, and it activates the cell-cycle checkpoint that prevents genetically damaged cells from dividing. "ATM is required for a B cell to know that it has a broken chromosome. And if it doesn't know that it seems to be able to keep on going," says Michel.

Since the ATM protein is mutated in a number of lymphomas -- cancers of the lymph and immune system -- the new finding suggests to researchers that the lymphocytes could have been living with DNA damage for a long time, and that this damage likely plays a role in later chromosomal translocations, rearrangements of genetic materials that can lead to cancer.

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St. Jude Study Yields Secrets of Chromosome Movement

Investigators at St. Jude Children's Research Hospital have used the lowly yeast to gain insights into how a dividing human cell ensures that an identical set of chromosomes gets passed on to each new daughter cell. Errors in this critical part of cell division can cause one daughter cell to get extra copies of some chromosomes that should have moved into the other daughter cell, or no copies of other chromosomes—a problem that is prevalent in cancer and can cause miscarriages or disease, such as Down syndrome.

St. Jude researchers made their discovery by tracking the activity of a small army of molecules with exotic names like argonaute (Ago1) and dicer; these molecules help maintain a specialized, tightly packaged form of DNA called heterochromatin at the part of the chromosome called the centromere. The investigators also showed the order in which certain critical events occur in setting up and maintaining this heterochromatin. The work is important because it gives scientists insight into how each daughter cell receives the normal number of chromosomes; and it offers important clues to understanding the genetic cause of certain catastrophic diseases. A report on this work appears in the May 25 issue of Molecular Cell.

All of the cell’s DNA is wrapped around a series of structures, called histone octamers, to generate chromatin—much like thread wound around a spool. This chromatin is then further compacted to form the characteristic, thick structures commonly recognized in illustrations and photographs as chromosomes. At the centromere, DNA is packaged into an even more compact and specialized form of chromatin called centromeric heterochromatin.

The centromere is the last point at which the two identical chromosomes are joined before the cell divides. Centromeric heterochromatin helps to yoke together the “sister chromatids” of each chromosome pair as they line up in the center of the dividing cell before separating and moving into their respective daughter cells. When the cell has ensured that it is safe to continue dividing, each sister chromatid moves in opposite directions toward the two new daughter cells that are forming.

“The cell must establish and then maintain centromeric heterochromatin to ensure that each chromosome pair is stable and securely linked together until it’s time to separate,” says Janet Partridge, assistant member of the St. Jude Department of Biochemistry. “Otherwise, the chromosome pairs would drift apart and leave daughter cells with too many or too few chromosomes.” Partridge is the report’s senior author.

The St. Jude team studied combinations of molecules in yeast called the RITS and RDRC complexes, which together with an enzyme called Clr4 (Suv39 in humans), establish and maintain centromeric heterochromatin in the yeast cell during a carefully choreographed series of steps.


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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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