The combination of estrogen plus progestin, which women stopped taking in droves following the news that it may increase their risk of breast cancer, may decrease their risk of colorectal cancer, according to a report published in the January issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.

“Compared to women who had never taken these hormones, the use of estrogen plus progestin was associated with a reduced risk of colorectal cancer,” said Jill R. Johnson, M.P.H., a doctoral student at the University of Minnesota School of Public Health.

The largest risk reduction, approximately 45 percent, was seen among women who had completed use of estrogen plus progestin five or more years previously.

Johnson and her colleagues extracted data from 56,733 postmenopausal women who participated in the Breast Cancer Detection Demonstration Project follow-up study.  Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998.  During an average 15 years of follow-up, Johnson and colleagues identified 960 new cases of colorectal cancer in this population.

Any use of estrogen therapy was associated with a 17 percent reduced risk in colorectal cancer.  Among those who used estrogen, the largest reductions were seen among those who were current users (25 percent reduced risk) and users of ten or more years duration (26 percent reduced risk).

Researchers also found a 22 percent reduced risk among those who had ever used estrogen plus progestin in combination.  They further found a 36 percent reduction in risk among those who had used progestin sequentially or less than 15 days per month.  Past users of estrogen plus progestin, who had stopped at least five years ago, had a 45 percent risk reduction.

Although Johnson’s study was not designed to look at biological mechanisms for the protective effect of estrogen therapy, she did say that previous research has suggested that hormones may play a role in decreasing levels of insulin-like growth factors, thereby reducing risk.  “The biological mechanism will need to be explored in further studies,” said Johnson.

Women who took beta carotene or vitamin C or E or a combination of the supplements had a similar risk of cancer as women who did not take the supplements, according to data from a randomized controlled trial in the December 30 online issue of the Journal of the National Cancer Institute.

Epidemiological studies have suggested that people whose diets are high in fruits and vegetables, and thus antioxidants, may have a lower risk of cancer.  Results from randomized trials that address the issue, however, have been inconsistent and have rarely supported that observation.

In the current study, Jennifer Lin, Ph.D., of the Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues tested the impact of antioxidant supplements on cancer incidence in a randomized controlled trial.  A total of 7,627 women who were at high risk of cardiovascular disease were randomly assigned to take vitamin C, vitamin E, or beta-carotene.

With an average of 9.4 years of follow-up time, there was no statistically significant benefit from antioxidant use compared with placebo in terms of disease risk or mortality due to cancer.  Overall, 624 women developed cancer and 176 died from cancer during the follow-up time.  Compared with placebo, the relative risk of a new cancer diagnosis was 1.11 for women who took vitamin C, 0.93 for women who took vitamin E, and 1.00 for women who took beta carotene.  None of these relative risks was statistically significantly different from 1.

“Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality,” the authors conclude.  “In our trial, neither duration of treatment nor combination of the three antioxidant supplements had effects on overall fatal or nonfatal cancer events.  Thus, our results are in agreement with a recent review of randomized trials indicating that total mortality was not affected by duration of supplementation and single or combined antioxidant regimens.”

In an accompanying editorial, Demetrius Albanes, M.D., of the National Cancer Institute, reviewed data from previous randomized controlled trials that examined supplement use and cancer incidence.  He noted that while the trial data reported by Lin are negative with respect to lowering cancer risk, there is valuable information uncovered that should not be overlooked.  There was a trend for a reduction in colon cancer with vitamin E supplementation, which has been observed in other studies.  Additionally, beta carotene use was associated with a modest excess of lung cancer, which is consistent with previous reports.

“Null trials or those with unexpected outcomes should not, however, be viewed as failures; they have and will con¬tinue to shed light on the causes of cancer and help us discover the means for its prevention,” the editorialist concludes.

Even though the U. S. Environmental Protection Agency (EPA) has given final approval for use of a new pesticide, regulators in California and other states are taking a closer look at the substance’s potential adverse health effects before allowing the chemical to be used, according to an article scheduled for the Oct. 27 issue of Chemical & Engineering News, ACS’ weekly newsmagazine.

In the article, C&EN Associate Editor Britt E. Erickson notes that EPA first considered approving the pesticide, methyl iodide, in 2006 as a replacement for methyl bromide —which is now being phased out because of environmental concerns that it may damage the ozone layer. Although methyl iodide appears unlikely to have that effect, it is toxic to nerve cells and may carry a risk of thyroid damage, cancer, and other adverse health effects.

At least one environmental group and some scientists opposed EPA’s approval of the pesticide, alleging that EPA had been secretive during the review process, failing to fully consider the chemical’s health effects, and they pointed to an apparent conflict of interest involving the pesticide’s manufacturer. States like California and Florida had their own concerns about the pesticide’s safety and decided to do their own risk assessments before allowing use of methyl iodide. Florida finished its assessment and approved the use of methyl iodide last July, but not before requiring additional safety measures beyond those required by EPA. California’s assessment is still ongoing, the article notes.

Researchers at Georgetown University Medical Center (GUMC) have successfully tested a genetic strategy designed to improve treatment of human infections caused by the yeast Candida albicans, ranging from diaper rash, vaginitis, oral infections (or thrush which is common in HIV/AIDS patients), as well as invasive, blood-borne and life-threatening diseases.Their findings confirm that inhibiting a key protein could provide a new drug target against the yeast, which inhabits the mucous membranes of most humans. The research was presented today at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America (ICAAC/IDSA) in Washington, DC.

“This is a genetically intelligent approach to target identification and drug design,” says the study’s lead author, Richard Calderone, PhD, professor and chair of the department of microbiology and immunology and co-director of the PhD program in the global infectious disease program at GUMC.

“Candida infections are often treatable, however, in patients that are immunocompromised following cancer chemotherapy, bone marrow transplantation, or surgery, diagnosis is often delayed, postponing therapy,” he says. “Also when drug-resistant yeast pathogens cause the infection, clinical management of the patient becomes a problem.”

Candida invasive, blood-borne infections are the fourth most common hospital-acquired infection in the United States, costing the healthcare system about $1.8 billion each year, Calderone says.

“More drug resistance is being seen clinically, so there is significant room for improvement in the therapies used today,” he says

This study continues research in which Calderone and his colleagues identified a protein, the product of the Ssk1 gene that Candida needs to infect its host. To date, this protein has not been found in humans or in animals, which means it could be “targeted” with a novel drug without producing toxicity because such an agent should only attack the fungus.

The researchers found that if the Ssk1 gene is deleted from Candida albicans, the “triazole” drugs that are now used to treat these diseases are much more effective in the laboratory. “This allows the triazole drugs to do their job,” Calderone says. “We propose that this finding might lead to other, possibly more effective, treatment options.”

In this study, the researchers used a gene microarray analysis to further understand what knocking out the Ssk1 gene does to the organism, and they discovered that the gene is critical to the pathogenic nature of the fungi.

What this means is that an Ssk1 inhibitor might work in synergy with a triazole or perhaps as an effective stand-alone drug to treat Candida infections, the researchers say. If it works in Candida, it may have broader activity in other pathogens because Ssk1p is found in other fungi.

“Using the genome of the organism to find genes to target is a logical approach to drug design,” he says. The researchers are now working with other groups to find the right agent to target the Ssk1protein.

Scientific research shows that certain genes can influence a person’s likelihood to contract particular diseases, cancer for example. New research at the Masonic Cancer Center, University of Minnesota demonstrates that genetic markers may also show a person’s likelihood to survive the disease.

A research study led by Brian Van Ness, Ph.D., has successfully identified combinations of genes associated with early clinical relapse of multiple myeloma, a cancer of the white blood cells that produce antibodies. These results raise the possibility that a patient’s genetic background exerts an important influence on the patient’s prognosis and response to treatment.

“Ultimately, the goal of this research is to predict drug efficacy and toxicity based on a patient’s genetic profile, and develop individualized assessments and predictions for the right drug, at the right dose, for the right patient,” Van Ness said. This approach offers the dual benefits of avoiding unnecessary treatment for patients less likely to respond to a particular drug, and targeting treatments to those who will benefit most.

The findings are reported in the current issue of the research journal BMC Medicine. Van Ness heads the University’s Department of Genetics, Cell Biology, and Development, and conducts research through the Masonic Cancer Center.

In this study, Van Ness and his colleagues used genetic information that the International Myeloma Foundation has gathered from myeloma patients worldwide through its program, Bank On A Cure®. This first-of-its-kind program involves several of the major treatment and research centers for myeloma worldwide and thousands of myeloma patients who donate DNA samples to the bank. The University of Minnesota houses one of the program’s two DNA banks (the other is in London), and Van Ness is co-director of the program.

“Although myeloma is considered a fatal disease, individual patients have widely varied rates of disease progression and response to treatment because of attributes encoded in their DNA,” Van Ness said.

According to Van Ness, the research study findings demonstrate that cancer outcomes differ because patients vary in the ways they absorb, distribute, metabolize, and transport drugs across cell membranes. Individual variations in genes that regulate these biologic processes may not only affect the effectiveness of the drug, but also can result in adverse side effects.

The findings from this study pave the way for similar investigations into other cancers, neurological and cardiovascular conditions, organ transplants, and other diseases.

Scientists at Dana-Farber Cancer Institute have identified a previously undetected trigger point on a naturally occurring “death protein” that helps the body get rid of unwanted or diseased cells. They say it may be possible to exploit the newly found trigger as a target for designer drugs that would treat cancer by forcing malignant cells to commit suicide.Loren Walensky, MD, PhD, pediatric oncologist and chemical biologist at Dana-Farber and Children’s Hospital Boston, and colleagues report in the Oct. 23 issue of the journal Nature that they directly activated this trigger on the “executioner” protein BAX, killing laboratory cells by setting in motion their self-destruct mechanism.

The researchers fashioned a peptide (a protein subunit) that precisely matched the shape of the newly found trigger site on the killer protein, which lies dormant in the cell’s interior until activated by cellular stress. When the peptide docked into the binding site, BAX was spurred into assassin mode. The activated BAX proteins flocked to the cell’s power plants, the mitochondria, where they poked holes in the mitochondria’s membranes, killing the cells. This process is called apoptosis, or programmed cell death.

“We identified a switch that turns BAX on, and we believe this discovery can be used to develop drugs that turn on or turn off cell death in human disease by targeting BAX,” said Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.

BAX is one of about two dozen proteins known collectively as the BCL-2 family. The proteins interact in various combinations leading to either the survival of a cell or its programmed self-destruction. Cancer cells have an imbalance of BCL-2 family signals that drives them to survive instead of dying on command.

The late Stanley Korsmeyer, MD, an apoptosis research pioneer and Walensky’s Dana-Farber mentor, had suggested that killer proteins like BAX could be activated directly by “death domains,” termed BH3, contained within a subset of BCL-2 family proteins. He hypothesized that this activating interaction was a fleeting “hit-and-run” event, making it especially challenging for scientists to study the phenomenon.

As suspected, the proposed BAX-activating interactions could not be captured by traditional methods. “When you tried to measure binding of the BH3 subunits to BAX, you couldn’t detect the interaction,” explained Walensky. He recognized, however, that the BH3 peptides being used in the laboratory didn’t retain the coiled shape of the natural BH3 domains that participate in BCL-2 family protein interactions. Walensky and his colleagues pioneered the design of “stapled” BH3 peptides, which contain a chemical crosslink that locks the peptides into their natural coiled shape. With biologically active shape restored, the stapled BH3 peptides bound directly to BAX and triggered its killer activity.

Defining how the activating peptides docked on BAX remained a formidable catch-22. In order to solve the structure of an interaction complex, it needed to be stable enough for analysis. In this case, the BH3 binding event itself triggers BAX to change its shape and self-associate to perform its killer function, rendering the activating interaction unstable by definition.

What if, Walensky proposed, you could set up the interaction of BH3 and BAX under laboratory conditions that caused it to be more stable or proceed in slow motion? The plan was to adjust the potency of the stapled BH3 peptide so that, according to Walensky, “it was good enough to bind BAX, yet activate it just a bit more slowly so that we could actually study the interaction.” The researchers would then look for any detectable shift in the three-dimensional structure of the BAX protein to help point them to the docking site.

The researchers used nuclear magnetic resonance (NMR) spectroscopy to monitor the arrangement of atoms in the protein. First authors of the Nature paper Evripidis Gavathiotis, PhD, of Walensky’s laboratory and Motoshi Suzuki, PhD, of Nico Tjandra, PhD,’s laboratory at the National Institutes of Health, succeeded in generating pure BAX protein that could be put into solution with the stapled BH3 peptide — the latter in increasing concentrations until it initiated a BH3-BAX interaction. Gavathiotis and Suzuki used the NMR technique to spot a group of BAX amino acids, the building blocks of proteins, which were affected by the addition of the stapled BH3 peptide.

“The discrete subset of amino acids that shifted upon exposure to the stapled BH3 peptide mapped to a completely unanticipated location on BAX,” said Walensky. The long-elusive binding site on BAX that initiates its killer activity was revealed. “Because BAX lies at the crossroads of the cell’s decision to live or die, drugs that directly activate BAX could kill diseased cells like in cancer and BAX-blocking drugs could potentially prevent unwanted cell death, such as in heart attack, stroke, and neurodegeneration,” said Walensky.

New research suggests that the identification and examination of key cell signaling events required for initiation and progression of cancer might be best accomplished at the single cell level.  The research, published by Cell Press in the October issue of the journal Cancer Cell, provides new insight that may lead to better diagnosis and treatment of some complex cancers.

Recent advances in flow cytometry, a technique that allows detailed examination of individual cells, have enabled simultaneous measurement of cell type and signaling pathways.  Lead study authors Dr. Garry P. Nolan from the Stanford University School of Medicine and Dr. Mignon L. Loh from the UCSF Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center were interested in determining whether examination of cellular signaling abnormalities caused by genetic mutations associated with cancer could provide a precise correlation between aberrant signaling events and disease physiology.

“We had a strong hunch that we could use ‘deranged’ cellular signaling to track how cancer cell populations behave at diagnosis through therapy, as well as during remission or return of the cancer,” explains Dr. Nolan.  “By measuring how signaling proteins respond to certain stimuli at diagnosis and which are modified by resistant cancers, we are essentially monitoring key highways that cancers use to drive their own growth.  The advantage of diagnosing a patient’s cancer at the single cell level provides us an approach for early detection of cancer and yield insights into how cancer cells are responding or adapting to therapy.  A byproduct of the single cell technique, when appropriately extended, is that we should eventually be able to predict those pathways cancer cells might be using to circumvent current therapies and more intelligently direct the patient towards alternative treatments.”

The researchers focused on juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative disorder of young children.  JMML is difficult to diagnose and has a complex molecular profile.  Although genetic lesions impacting Ras signaling and alterations downstream of the activated GM-CSF receptor (both linked with inappropriate cell growth and survival) have been linked with JMML, there are very few methods for identifying therapeutic agents and assessing efficacy in JMML patients.

The researchers used flow cytometry to profile signaling at the single cell level, including molecules associated with GM-CSF and Ras signaling, for the presence of primary JMML cells with altered signaling behavior that correlated with disease physiology.  Cells samples came from JMML patients, healthy individuals and patients with other myeloproliferative disorders, some who had initially been diagnosed with JMML.  An unexpected STAT5 signaling signature was seen in most of the JMML patients, suggesting a critical role for JAK-STAT signaling in the biological mechanism of this cancer and suggesting potential targets for future therapies.

“This work successfully used single-cell profiling to follow patients over time and show that disease status in JMML – at diagnosis, remission, relapse and transformation – was indicated by a subset of cells with an abnormal signaling profile,” says Dr. Loh.  “Revealing cell subpopulations, even rare cells, that are associated with disease opens additional avenues for measuring minimal residual disease, assessing biochemical effects of targeted therapies at the single cell level and understanding drug actions and mechanisms of diseases of heterogeneous origins and manifestations in diverse patient populations.”

Caswell et al.report in the Journal of Cell Biology how the altered behavior of integrins can prompt metastatic movement in tumor cells.

On 2D surfaces, cells may migrate randomly, or be strongly unidirectional.  Integrins, which link the cell to the extracellular matrix, are known to influence the mode of migration, but exactly how has been unclear.  Recent work has suggested that an integrin called a5b1 drives random movement, while an integrin called avb3 has been associated with unidirectional migration—the balance of activity between the two determining the type of movement.  To further explore the contribution of a5b1 to random migration, the authors thus blocked avb3.

The treated cells changed their mode of migration from unidirectional to random, and their ability to invade 3D gels increased.  The changed behavior correlated with an increase in trafficking of a5b1 from intracellular compartments to anterior membrane protrusions.  But this increase in trafficking did not significantly alter a5b1’s contribution to cell adhesion—the ease with which cells were dislodged from a spinning disk increased as the amount of avb3 was reduced, but was not correlated with any change in a5b1.  This suggested that the cells’ increased invasive ability was due to alteration in some other property.  That property turned out to be activation of a proinvasive pathway headed by a kinase called Akt.

In avb3-blocked cells, a5b1 became associated with epidermal growth factor receptor 1 (EGFR1), which increased EGFR1’s abundance at the membrane protrusions, as well as its autophosphorylation.  Because EGFR1 is an activator of the Akt pathway, hey presto, the cells took on some new moves.

A Northwestern University research team has developed a promising nanomaterial-based biomedical device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

The flexible microfilm device, which resembles a piece of plastic wrap and can be customized easily into different shapes, has the potential to transform conventional treatment strategies and reduce patients’ unnecessary exposure to toxic drugs.  The device takes advantage of nanodiamonds, an emergent technology, for sustained drug release.

The researchers demonstrated that the device releases the chemotherapy agent Doxorubicin in a sustained and consistent manner -a requirement of any implanted device for localized chemotherapy.  The results of the study are published online today (Oct.  2) by the journal ACS Nano.

“The thin device -a sort of blanket or patch -could be used to treat a localized region where residual cancer cells might remain after a tumor is removed,” said Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science, who led the research.

If a surgical oncologist, for example, was removing a tumor from the breast or brain, the device could be implanted in the affected area as part of the same surgery.  This approach, which confines drug release to a specific location, could mitigate side effects and complications from other chemotherapy treatments.

“Several surgeons at Northwestern’s Feinberg School of Medicine, as well as other medical schools and hospitals, are very interested in the device because it is biocompatible and provides such stable and consistent drug release,” said Ho, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In their study, Ho and his colleagues embedded millions of tiny drug-carrying nanodiamonds in the FDA-approved polymer parylene.  Currently used as a coating for implants, the biostable parylene is a flexible and versatile material resembling plastic wrap.  A substantial amount of drug can be loaded onto clusters of nanodiamonds, which have a high surface area.  The nanodiamonds then are put between extremely thin films of parylene, resulting in a device that is minimally invasive.

To test the device’s drug release performance, the researchers used Doxorubicin, a chemotherapeutic used to treat many types of cancer.  They found the drug slowly and consistently released from the embedded nanodiamond clusters for one month, with more Doxorubicin in reserve, indicating a more prolonged release (several months and longer) was possible.  The device also avoided the “burst” or massive initial release of the drug, a common disadvantage with conventional therapy.

In control experiments, where the drug was present but without the nanodiamonds, virtually all of the drug was released within one day.  By adding the drug-laden nanodiamonds to the device, drug release was instantly lengthened to the months-long timescale.

In addition to their large surface area, nanodiamonds have many other advantages that can be utilized in drug delivery.  They can be functionalized with nearly any type of therapeutic.  They can be suspended easily in water, which is important for biomedical applications.  The nanodiamonds, each being four to six nanometers in diameter, are minimally invasive to cells, biocompatible and do not cause inflammation, a serious complication.  And they are very scalable and can be produced in large quantities.

The architecture of the device is amenable to housing small molecule, protein, antibody or RNAor DNA-based therapeutics.  This gives the technology the potential to impact a range of treatment strategies where implanted, long-term drug release is needed.

Ho and his research group previously pioneered the application of nanodiamonds for systemic drug-carrying applications.  This new work successfully transitions the nanodiamonds from basic materials to serving as a foundation for device manufacturing.

To build the biomedical device, the researchers developed a streamlined approach where a double layer of parylene was fabricated, with the nanodiamond-drug complexes sandwiched in between.  The bottom layer, approximately 20 to 30 microns thick, serves as the backbone of the device, allowing it to be easily handled.  For the top layer, the research team created a thinner semi-porous film that allows the drug to slowly release from the device.

“One of the most significant aspects of this work is that the fabrication procedures are highly scalable, meaning hundreds, or even thousands, of devices potentially could be manufactured in parallel and at low cost,” said Ho.

“The nanodiamonds are quite economical and have already been mass-produced as lubrication components for automobiles and for use in electronics,” added Robert Lam, a graduate student in Ho’s research group and the article’s lead author.

In the area of localized chemotherapy, the team hopes that this technology will bring new levels of treatment efficacy that can complement injected chemotherapy to reduce dosages and decrease devastating side effects.

Because of the proven biocompatibility and massively parallel deposition capabilities of parylene, the researchers are engaged with pre-clinical trials of the nanodiamond-embedded parylene.

Using computer models and live cell experiments, biomedical engineers at the Johns Hopkins University School of Medicine have discovered more than 100 human protein fragments that can slow or stop the growth of cells that make up new blood vessels.

Reporting online last week in the Proceedings of the National Academy of Sciences, the researchers say the findings could lead to developing treatments to fight diseases that depend on the growth of new blood vessels, including cancer, macular degeneration and rheumatoid arthritis.

“Before, there were only 40 known antiangiogenesis peptides,” says Aleksander Popel, Ph.D., a professor of biomedical engineering at Hopkins.  “Now, using a whole-genome, computer-based approach, we have identified more than 100 new ones, all of which can be further researched for their ability to fight the more than 30 known diseases affected by excessive blood vessel growth.”

To identify short protein fragments — peptides — that can block blood vessel growth, the team started by looking at 40 known peptides that have been studied and characterized by other experts in the field to stop blood vessel growth in animal models of disease.  Working under the assumption that the antivessel activity of these peptides can be attributed to similar features that are shared by a number of proteins, like the sequence of the peptide building blocks, the team first categorized the 40 known peptides by where they are located and what they look like.

Having defined nine families, the researchers then used computer programs and compared the peptide families to all of the proteins encoded by the genome.  They found more than 120 peptides contained in 82 different proteins, many of which were not previously known to have any activity on blood vessel development.

“Computational methods only identify potential candidates,” says Popel.  “We next had to do the experiments on live cells to see if they had any real activity.  Of the 82 proteins we identified, most were not previously known to have any antiangiogenic activity.”

To test the activity of these candidate peptides, the researchers applied them to blood vessel cells growing in the lab and examined whether they had any effect on the growth, survival and movement of these cells.  To test growth and survival, they added different amounts of peptide to dishes containing roughly 2,000 cells and after three days, counted how many cells were still alive.

To test cell movement, they placed cells in double-chambered dishes and treated the cells with a growth factor known to encourage cells to move.  To some of the dishes they added the test peptides.  After 20 hours, they measured the number of cells that had crawled from one chamber to the other.  They then identified the protein receptors that the peptides bind to and were able to show in some cases that combinations of more than one peptide were better able to stop the cells than using single peptides.

“Basic, computational studies like this are critical to understanding normal blood vessel growth,” says Popel.  “A better understanding of normal growth gives us a better idea of what happens in disease.”

The next step, Popel says, is to test these peptides in animal models of human disease and to identify the diseases most appropriately treated by these newly identified peptide inhibitors.

Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development.  The study, published October 3rd in the open-access journal PloS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.

EBV is a common herpesvirus whose latent infection is strongly associated with several types of cancer including NPC, a tumor that is endemic in several parts of the world.  With NPC only a few EBV proteins are expressed, including EBNA1.  EBNA1 is required for the persistence of the EBV genomes, however, whether or not EBNA1 directly contributes to the development of tumors has not been clear, until now.

In this study Frappier and her team examined PML nuclear bodies and proteins in EBV-positive and EBV-negative NPC cells.  Manipulation of EBNA1 levels in each cell type clearly showed that EBNA1 expression induces the loss of PML proteins and PML nuclear bodies through an association of EBNA1 with the PML bodies.  PML nuclear bodies are known to have tumor-suppressive effects due to their roles in regulating DNA repair and programmed cell death, and accordingly, EBNA1 was shown to interfere with these processes.

The researchers conclude that there is “an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.”  Since EBNA1 is expressed in all EBV-associated tumors, including B-cell lymphomas and gastric carcinoma, these findings raise the possibility that EBNA1 could play a similar role in the development of these cancers.  The cellular effects of EBNA1 in other EBV-induced cancers will require further investigation.

Contrary to a long-standing assumption that blood vessel cells in healthy tissues and those associated with tumors are similar, a new study unequivocally demonstrates that tumor blood vessel cells are far from normal.  The research, published by Cell Press in the September issue of the journal Cancer Cell, identifies tumor-specific blood vessel cells that are atypically stem cell-like and have the potential to differentiate into cartilageor bone-like tissues.

Although it has been known for some time that tumors can be eradicated in mice by targeting their blood supply, very little is known about the biology of the endothelial cells that line tumor blood vessels (TECs).  “A primary assumption of antiangiogenesis therapy is that TECs are normal and derived from nearby, preexisting vessels,” explains senior author Dr. Michael Klagsbrun from Children’s Hospital Boston and Harvard Medical School.  “However, we and other groups have shown that there are several key differences between normal and tumor endothelium.”

Dr. Klagsbrun and lead author Dr. Andrew Dudley isolated TECs from mice that spontaneously develop prostate tumors very similar to human prostate cancers.  The researchers found that the TECs were multipotent, meaning that they were not fully mature and had the potential to differentiate into multiple different types of cells.  The isolated TECs differentiated to form cartilageand bone-like tissues.  “These results suggest that TECs possess a stem/progenitor cell property that distinguishes them from Ecs throughout the normal vasculature and undergo atypical differentiation,” explains Dr. Klagsbrun.

The researchers went on to demonstrate blood vessel calcification in human and mouse prostate tumor specimens.  This bone-like calcification has also been described in diseased blood vessels and is likely to have clinical significance in prostate cancer.  “It is possible that calcification of tumor blood vessels could impair blood flow or enable tumor cell entry into the bloodstream, facilitating metastasis,” offers Dr. Klagsbrun.  “Further, the expression of bone-specific proteins in prostate tumor cells may enable their survival once they reach the bone microenvironment.”

Additional research is required to determine how the atypical properties of TECs are associated with the tortuous, leaky vessels characteristic of tumors and whether vascular calcification does indeed encourage tumor cell metastasis.  It is also possible that vascular calcification, which is easily discernible histologically, may be a useful diagnostic criterion.

Scientists have gained new insight into a mechanism whereby chemotherapy may actually assist the rapid regrowth of tumors after treatment.  The research, published by Cell Press in the September issue of the journal Cancer Cell, also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede the devastating tumor recovery that often follows cancer therapy.

“Chemotherapy remains the most commonly employed form of systemic cancer treatment.  However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors,” says senior study author Dr. Robert S. Kerbel from the University of Toronto.

Clinical trials have indicated that drugs that inhibit the growth of blood vessels, called antiangiogenic drugs, can sometimes enhance the effectiveness of traditional chemotherapy.  For example, coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel improves survival benefits for metastatic breast cancer and small cell lung cancer.  In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.

“Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy,” says author Dr. Yuval Shaked.  Drs.  Kerbel, Shaked, and colleagues had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.

The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to impact CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness.  They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not.  They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.

“Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy,” explains Dr. Kerbel.  “Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug.”

Using an engineered common cold virus, UCLA researchers delivered a genetic payload to prostate cancer cells that allowed them, using Positron Emission Tomography (PET), to locate the diseased cells as they spread to the lymph nodes, the first place prostate cancer goes before invading other organs.

The tiny cancer metastases in the pelvic lymph nodes are very difficult to find using conventional imaging tools such as CT scanning. This discovery could aid oncologists in finding the cancer’s spread earlier, when it’s more treatable, and before it invades distant organs, said Lily Wu, a researcher at UCLA’s Jonsson Cancer Center and the senior author of the study.

The next step for Wu and her colleagues is linking the non-invasive imaging advance with a treatment component, activating a toxic agent in the genetic payload to kill the spreading cancer cells. Wu hopes one day to be able to find tiny prostate cancer metastases in patients and kill them at the same time, watching it all on a PET scanner. She currently is refining this image-guided therapy in her lab in mouse models.

“I think this is very exciting for many reasons,” said Wu, who also is an associate professor of pharmacology and urology. “We now know we can reach these prostate cancer metastases at an earlier stage than before, and we know we can deliver genes to those cancer cells that produce proteins that can be imaged by PET. Now we will find out how effective this genetic toxic payload is in preventing further spread of the cancer to other vital organs.”

The study appears July 11, 2008 in the early, online edition of the peer-reviewed journal Nature Medicine.

The spread of prostate cancer to the pelvic lymph nodes is the most reliable indicator that the patient will have a poor prognosis, with disease recurrence and progression likely. Accurately assessing pelvic lymph node involvement in patients is critical in planning their treatment, Wu said.

Currently, physicians don’t know if a treatment is attacking cancer cells until, using traditional imaging, they see a decrease in tumor size, an insensitive approach that can take weeks and months. And if the treatment isn’t working, the patient is exposed to a toxic therapy that isn’t helping them. If Wu is successful, an oncologist would know within days if the cancer has spread and whether the treatment is killing the cancer.

Using mouse models, Wu and her team engineered a virus to travel to the lymph nodes, using a prostate cancer-specific vector that dictates s its protein payload be expressed only in prostate cells. The payload in this case is a protein that can be imaged by PET scanning. The virus was introduced into the tumor in the mouse and Wu and her team were able to detect PET signals only from the lymph nodes with cancer cell involvement, indicating the virus reached and infected the prostate cancer cells and produced the imaging protein.

As part of this study, Wu co-developed TSTA, a two-step transcriptional amplification method, which increased the expression of the genetic payload inside the cancer cells – in effect boosting the imaging signals and potential killing activity of the engineered virus.

Wu believes this type of image-guided therapy has the potential to improve the way advanced prostate cancer is treated.

“It would represent a treatment advance in patients for whom outcome is not good,” Wu said. “This would help improve the prognosis for these patients by letting us find and treat these metastases early. If we can catch the cancer before it invades other organs, we have a better chance to change the outcomes for these patients.”

This type of approach was pioneered in the field of breast cancer with testing of the sentinel lymph node, the first place breast cancer goes when it spreads. A biopsy can determine if the cancer is in the sentinel node, therefore spreading, and oncologists base their treatment decisions on that information. In prostate cancer, the lymph nodes are much more difficult to access for biopsy, so Wu’s method provides a much needed, non-invasive alternative.

Among patients with castration-resistant prostate cancer, the addition of hormone therapy following vaccine treatment improved overall survival compared with either treatment alone or when the vaccine followed hormone treatment, according to recent data published in the July 15 Clinical Cancer Research, a journal of the American Association for Cancer Research.

Philip M. Arlen, M.D., director of the Clinical Research Group for the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, at the National Cancer Institute, said the findings have important implications for guiding treatment decisions for prostate cancer patients.

“Vaccines, if and when they are approved, can be safely and effectively combined with other therapies, including hormones,” said Arlen.  “There appears to be an advantage in overall survival.”

Arlen and colleagues enrolled 42 patients who had castration-resistant prostate cancer.  These patients were randomly assigned to receive either a poxvirus-based prostate-specific antigen vaccine or hormone therapy with nilutamide.  At progression, patients received the other therapy and continued to receive their original therapy.

For all the patients enrolled in the study, the three-year survival probability was 71 percent and the median overall survival was 4.4 years.  Patients randomized to the vaccine had a three-year survival probability of 81 percent and an overall survival of 5.1 years, while patients taking nilutamide had a three-year survival probability of 62 percent and an overall survival of 3.4 years.

Of the 42 patients in the study, 12 patients who were originally assigned to vaccine switched to nilutamide plus vaccine and eight patients who were originally assigned to nilutamide switched to vaccine plus hormone, due to rising levels of prostate-specific antigen with no evidence of metastasis.  For patients who received vaccine and then nilutamide, the three-year survival probability was 100 percent with a median overall survival of 6.2 years.  For patients who switched to the vaccine after hormone, the three-year survival probability was 75 percent with a median overall survival of 3.7 years.

Arlen said the hormone therapy in combination with the vaccine works in two ways.

“By using hormone therapy in prostate cancer you can help enhance your T-cell response to where the cancer is in the prostate gland, and you are also more likely to achieve a better immune response,” said Arlen.

Building on the results of this phase II study, researchers have developed another generation of this vaccine by adding molecules which boost T-cell responses.

Based on the current pace of vaccine research overall, Arlen predicts that men with prostate cancer could potentially see an effective, new treatment vaccine within the next several years.

“Phase II trials such as this one are adding to our knowledge, and other phase III trials are getting ready to publish their data,” said Arlen.  “If the phase II data hold up in phase III trials, we could see a new treatment vaccine within a few years.”