Research

Medical News Release

• Men's Health News, Published: 2008 Sept 15

Scientists at Sunnybrook Research Institute (SRI) are developing and commercializing a promising novel therapy for the treatment of prostate cancer that may offer patients a faster and more precise treatment than existing clinical alternatives, with fewer side effects.
The new treatment-magnetic resonance imaging (MRI)-guided transurethral ultrasound-uses heat from focused ultrasound to treat cancer in the prostate gland precisely while sparing the delicate noncancerous tissues around the prostate essential for healthy urinary, bowel and sexual function.

Sunnybrook researchers Dr. Michael Bronskill and Dr. Rajiv Chopra have licensed their innovation and formed Profound Medical Inc., which will develop the technology for clinical use.

Unlike surgical removal of the prostate, the treatment is minimally invasive and could be performed without a lengthy hospital stay. In preclinical studies, treatment takes less than 30 minutes. The therapy, on which clinicians at Sunnybrook will conduct preliminary testing in preparation for a clinical trial, could help limit the number of men living with the common, debilitating and often permanent side effects of surgery and radiation treatments currently used. More of these invasive therapies are being performed now because improved awareness among younger men has converged with better clinical detection tools.

Profound's clinical development is targeted at treatment that reduces the high level of incontinence and impotence associated with current, invasive treatments. The therapy involves two different and naturally incompatible technologies, ultrasound and MRI, which Bronskill and Chopra spent 10 years making compatible. "You have to make an ultrasound heating applicator work inside a magnetic resonance imager, without the two technologies interfering with each other," says Bronskill, who is a professor at the University of Toronto. "The prostate cancer site is a natural for this technology because it's surrounded by structures you want to spare."

Dr. Laurence Klotz, chief of urology at Sunnybrook Health Sciences Centre, and a professor at the University of Toronto, says that a noninvasive therapy for early, localized prostate cancer could improve the quality of life of hundreds of thousands of men. "The key to effective noninvasive treatment is accurate imaging of the target organ and of the effects of the treatment on tissue. In that respect, MR-guided ultrasound has many potential advantages over transrectal ultrasound-guided focused ultrasound, now approved for use in Canada," says Klotz.

The scientists' creation of this clinically viable product was done in a setting committed to commercialization. "At SRI, we are dedicated not only to developing new and better therapies and technologies, but also to getting those discoveries to our patients," says Dr. Michael Julius, vice-president of research at Sunnybrook. Profound Medical Inc. is the third imaging-technology company to be spun out of research at SRI in recent years. The other two are VisualSonics Inc. and Sentinelle Medical Inc.

• Medical Research News, Published: 2008 August 20

Turning up the heat on the red tomato during processing has the potential to give the popular garden staple added disease-fighting power, Ohio State University research suggests.

Scientists have found that lycopene molecules in tomatoes that are combined with fat and subjected to intense heat during processing are restructured in a way that appears to ease their transport into the bloodstream and tissue. The tomato is the primary food source of lycopene, a naturally occurring pigment linked to the prevention of cancer and other chronic diseases.

In its standard structure in the average red tomato, the lycopene molecule is laid out in a linear configuration. That structure seems to hinder the molecule's absorption through intestinal walls and into the blood, said Steven Schwartz, an investigator in Ohio State's Comprehensive Cancer Center and a professor of food science and technology at Ohio State.

Meanwhile, most of the lycopene that is found circulating in human blood is configured in a bent molecular form. This means that either the human body somehow transforms lycopene molecules through reactions that have yet to be identified, or that the bent molecular structures of lycopene are much more likely to be absorbed into the blood and transported to tissue - a necessary step in preventing disease.

Assuming the latter is true, Schwartz and colleagues have devised a way to process red tomatoes - the variety preferred by American consumers - into a sauce that contains bent molecular forms of lycopene. A clinical trial conducted in collaboration with Steven Clinton, a medical oncologist and physician scientist in Ohio State's Comprehensive Cancer Center, showed that people had more lycopene in their blood after eating the specially processed sauce than they did after eating regular red tomato sauce.

Schwartz described the research today (8/20) at the American Chemical Society meeting in Philadelphia.

In the food science world, processing gets a bad rap for its tendency to deplete vegetables of nutrients, change their color and often negatively affect how they taste.

"Instead, here is a case where processing is positive in terms of enhancing absorption of lycopene," said Schwartz.

Lycopene belongs to a family of antioxidants called carotenoids, which give certain fruits and vegetables their distinctive colors. Carotenoids' antioxidant properties are associated with protecting cells and regulating cell growth and death, all of which play a role in multiple disease processes.

In its natural state, lycopene in a red tomato is in what is called an all-trans configuration, characterized by its linear form. The molecular structure of lycopene circulating in human blood is in what is called a cis-isomer configuration, or a bent form. The chemical properties are the same - only the configuration differs.

"What we have found is we can take the red tomato molecular form of lycopene and by processing it and heating it in combination with added oil, we can change the shape of the molecule so it is configured in this bent form," Schwartz said.

Heat is essential to the process, but so is adding some fat, Schwartz said. In previous work, he and colleagues determined that consuming fat and carotenoids simultaneously improved absorption of lycopene and other compounds, but the scientists weren't sure exactly why.

When humans eat fats, or lipids, the body produces tiny droplets of fat called lipid micelles during digestion that are easily taken up through the intestinal wall and absorbed into the bloodstream.

Continuing research has led Schwartz to hypothesize that lycopene in its linear form tends to stack and become crystallized, which lowers, but does not eliminate, its absorption potential. But the bent forms of lycopene are able to more easily find their way into the lipid micelles during digestion, and increasing amounts of the antioxidant in that form are more likely to be transported to the blood along with the fats.

Taking all this into consideration, the researchers processed red tomatoes into two kinds of sauce: a sauce rich in cis-lycopene, the bent configuration, and a sauce containing mostly all-trans-lycopene, the linear form. Both sauces were flavored similarly and initially heated using the same methods. Corn oil was added to both sauces as well. But the sauce designed to produce lycopene in the bent molecular forms was subjected to a second round of heating at 260 degrees Fahrenheit for 40 minutes. The resulting sauce contained nine times more cis-isomers than the regularly processed sauce.

Twelve people participated in a study of the sauces, and all ate both kinds of sauce over the course of the study. After each meal, researchers took samples of participants' blood seven times during the following 9 1/2 hours to measure lycopene levels. The scientists used a special testing method to analyze lycopene levels in the blood associated only with the tomato sauce meal, avoiding any other possible sources of those compounds in the bloodstream.

Research participants had a 55 percent increase in total lycopene absorption after eating the specially processed sauce when compared to their lycopene blood levels after eating the regular sauce. This finding reinforced the expectation that the bent forms of lycopene are more easily absorbed into human blood, Schwartz said.

Details of this study were first published in the British Journal of Nutrition in 2007. Additional clinical trials are ongoing.

Schwartz said most currently available commercial products don't contain the bent forms of lycopene molecules. But he noted that some home cooking practices might be able to produce the same results as the special processing method he and colleagues designed.

"Some people like to cook tomato sauce for prolonged periods, sometimes reheating it day after day, because it tastes better on the second and third day. They add fat by using oil or meat, and that's going to start to induce cis-isomers of lycopene if fat is present and the cooking continues," Schwartz said. "So it's possible people could induce this process and increase lycopene absorption by routine food preparation procedures, as well."

• Miscellaneous News News, Published: 2008 July 21

An elderly man in Britain believes he has beaten cancer by drinking a daily glass of broccoli juice.

Ray Wiseman, a 79 year old grandad was diagnosed with bladder cancer in 2003, at the time his prognosis was not good and Ray was not expected to survive.

However recent scans have revealed that the cancer has stopped spreading and his chances of a recovery have greatly improved.

Mr Wiseman attributes the turn around in his condition to the tumbler of broccoli juice that his wife prepares for him each day.

Mr Wiseman, who lives in Leicestershire, says he knows the daily juice has done him some good and suggests it could do the same for others.

The idea came from his wife Joan who is herself 72, after a friend told her about the healing benefits of green vegetables.

The daily cocktail is a combination of a head of broccoli with some apples and carrots which improve the taste and Joan says her husband's incredible luck is down to the broccoli.

Joan believes their experience could help other cancer sufferers.

Cancer Research UK have asked for the recipe so their scientists can carry out studies into the vegetable's benefits.

Recent research has suggested that broccoli might possibly have cancer-beating properties - scientists at the Institute of Food Research found that men who ate one daily portion had altered patterns of gene activity in their prostates, suggesting that the chemicals in the vegetable might be able to reduce the risk of prostate cancer.

Back in 2006 a report published in the British Journal of Cancer found that natural chemicals in certain vegetables, such as broccoli-cauliflower and cabbage, can enhance DNA repair in cells, which could help stop them becoming cancerous.

Cancer Research UK says a lot of research has focused on broccoli and its healing properties and it should be part of a healthy diet that is high in all fruit and vegetables.

Bladder cancer is the fifth most common form of the disease and affects more men than women.

Broccoli is a member of the cabbage family and is rich in vitamin C and also has properties that boost the human immune systems helping to fight viruses, bacteria and cancer.

Research has found that boiling broccoli can reduce its anti-cancer compounds, while steaming and microwaving do not.

• Medical Research News, Published: 2008 July 9

Using a miniature laboratory-on-a-chip device, a team of investigators at the Massachusetts General Hospital, led by Daniel Haber, M.D., Ph.D., and Mehmet Toner, Ph.D., both members of the MIT-Harvard Center for Cancer Nanotechnology Excellence (CCNE), has developed a method that detects and analyzes the genetic signature of rare tumor cells in the bloodstream.
The results from this analysis allowed the researchers to identify those patients most likely to respond to a specific targeted treatment. This chip-based analysis also allowed the researchers to monitor genetic changes that occur during therapy.

According to Dr. Haber, this chip opens up a new field of studying tumors in real time. "When the device is ready for larger clinical trials, it should give us new options for measuring treatment response, defining prognostic and predictive measures, and studying the biology of blood-borne metastasis, which is the primary method by which cancer spreads and becomes lethal." Dr. Haber and his team published their results in The New England Journal of Medicine.

Circulating tumor cells (CTCs) are living solid-tumor cells found at extremely low levels in the bloodstream. Until the development of the CTC-chip by the Massachusetts Institute of Technology (MIT)-Harvard CCNE team, it was not possible to get information from CTCs that would be useful for clinical decision-making. The current study was designed to determine whether the device could go beyond detecting CTCs to helping analyze the genetic mutations that can make a tumor sensitive to treatment with targeted therapy drugs.

The researchers tested blood samples from patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the United States. In 2004, cancer researchers had discovered that mutations in a protein called epidermal growth factor receptor (EGFR) determine whether NSCLC tumors respond to a group of drugs called tyrosine kinase inhibitors (TKIs), which includes gefitinib (Iressa) and erlotinib (Tarceva). Although the response of sensitive tumors to those drugs can be swift and dramatic, eventually many tumors become resistant to the drugs and resume growing.

The CTC-chip was used to analyze blood samples from 27 patients-23 who had EGFR mutations and 4 who did not-and CTCs were identified in samples from all patients. Genetic analysis of CTCs from mutation-positive tumors detected those mutations 92 percent of the time. In addition to the primary mutation that leads to initial tumor development and TKI sensitivity, the CTC-chip also detected a secondary mutation associated with treatment resistance in some participants, including those whose tumors originally responded to treatment but later resumed growing.

Blood samples were taken at regular intervals during the course of treatment from four patients with mutation-positive tumors. In all of those patients, levels of CTCs dropped sharply after TKI treatment began and began rising when tumors resumed growing. In one patient, adding additional chemotherapy caused CTC levels to drop again as the tumor continued shrinking.

Throughout the course of therapy, the tumors' genetic makeup continued to evolve. Not only did the most common resistance mutation emerge in tumors where it was not initially present, but new activating mutations-the type that causes a tumor to develop in the first place-appeared in seven patients' tumors, indicating that these cancers are more genetically complex than expected and that continuing to monitor tumor genotype throughout the course of treatment may be crucial.

"If tumor genotypes don't remain static during therapy, it's essential to know exactly what you're treating at the time you are treating it," says Haber. "Biopsy samples taken at the time of diagnosis can never tell us about changes emerging during therapy or genotypic differences that may occur in different sites of the original tumor, but the CTC-chip offers the promise of noninvasive continuous monitoring."

This work, which was supported in part by the National Cancer Institute's Alliance for Nanotechnology in Cancer, is detailed in the paper "Detection of Mutations in EGFR in Circulating Lung-Cancer Cells." An abstract of this paper is available through PubMed.

• Medical Research News, Published: 2008 June 2

Chronic inflammation of the intestine or stomach can damage DNA, increasing the risk of cancer, MIT scientists have confirmed. The researchers published evidence of the long-suspected link in the June 2 online issue of the Journal of Clinical Investigation (JCI).

In two studies, the researchers found that chronic inflammation accelerated tumor formation in mice lacking the ability to repair DNA damage.

"It's something that was expected but it was never formally proven," said Lisiane Meira, research scientist in MIT's Center for Environmental Health Sciences (CEHS) and lead author of the paper.

The results of this work suggest that people with decreased ability to repair DNA damage might be more susceptible to developing cancer associated with chronic inflammation such as ulcerative colitis, Meira said.

Inflammation caused by infectious agents such as Helicobacter pylori and Hepatitis C is known to increase the risk of stomach and liver cancers, respectively. Researchers have long known that inflammation produces cytokines (immune response chemicals that encourage cell proliferation and suppress cell death), which can lead to cancer.

In addition, it was suspected that another effect of the inflammation pathway could also induce cancer. During the inflammatory response to infection, immune cells such as macrophages and neutrophils release reactive oxygen and nitrogen species that can damage DNA.

Under normal circumstances, the DNA damage induced during an inflammatory response is repaired by DNA repair systems. But, if the DNA repair system is not functioning properly, that damage can induce mutations that can lead to cancer, according to the new study.

Every individual has variations in the effectiveness of their DNA repair systems, which could help doctors figure out which patients are most susceptible to inflammation-induced cancers.

"That variation could influence the susceptibility of individuals and how they are going to respond to a chronic inflammation response," said Leona Samson, senior author of the study and director of the CEHS.

In the JCI study, the researchers induced colon inflammation in the mice by treating them with a chemical compound that creates a condition similar to human colitis. "Lo and behold, the DNA repair deficient mice were more susceptible" to cancer, said Meira.

To show that this is a general phenomenon, the team did a second study, in collaboration with another CEHS member, James Fox, director of the Division of Comparative Medicine at MIT, and one of his students, Chung-Wei Lee. They showed that mice infected with H. pylori, who also lacked the proper DNA repair mechanisms, were more susceptible to pre-cancerous lesions in the stomach.

This study is related to another recent paper published by Fox, which found that treating H. pylori infection early with antibiotics can prevent cancer development. The new study suggests that if H. pylori goes untreated, patients with poorly functioning DNA repair mechanisms would have a greater risk of developing cancer.

• Medical Studies/Trials, Published: 2008 April 21

Cancer treatment with chemotherapeutic agents is often associated with delayed adverse neurological consequences - an occurrence often referred to as "chemobrain" - that may compromise the quality of life of a proportion of cancer survivors.

Now, research published in the open access Journal of Biology demonstrates that treatment with a single chemotherapeutic agent, 5-fluorouracil (5-FU), by itself is sufficient to cause a syndrome of delayed degeneration in the central nervous system (CNS). 5-FU is a widely used chemotherapeutic agent that is employed, alone or in combination with other agents, in the treatment of cancers of the colon, rectum, breast, stomach, pancreas, ovaries and bladder.

Little is known about the side-effects of chemotherapy on the CNS, despite their obvious clinical importance. Until now researchers have not fully understood the underlying biology, including whether these effects require: exposure to multiple chemotherapeutic agents; chemotherapeutic agents plus the body's own response to cancer; blood-brain barrier damage; or inflammation. Clinicians have also lacked animal models to study this important problem.

Professor Mark Noble and colleagues of the University of Rochester Stem Cell and Regenerative Medicine Institute and the Harvard Medical School, Boston discovered that short-term systemic administration of 5-FU to mice caused both acute CNS damage and a syndrome of progressively worsening delayed damage. This damage was not self-repairing, and instead became worse over time. In addition, Noble and colleagues also demonstrated that treatment with chemotherapy also had delayed effects on the speed with which information is transferred from the ear to the brain.

Myelin sheaths are necessary for normal neuronal function. One key finding of the study was that clinically relevant concentrations of 5-FU were toxic not only for dividing cells of the CNS but also for the cells that produce the insulating myelin sheaths (non-dividing oligodendrocytes). The delayed damage the researchers measured was to the myelinated tracts of the CNS and associated with extensive myelin pathology. The findings regarding the speed of ear-to-brain information transfer may offer a non-invasive means of analyzing myelin damage associated with cancer treatment.

"Multiple clinical reports have identified neurotoxicity as a complication of treatment regimens in which chemotherapeutic agents such as 5-fluorouracil are components," says Noble. "As treatments with chemotherapeutic agents will clearly remain the standard of care for cancer patients for many years to come, the need to better understand such damage is great."

Professor Noble continues "These studies extend the field of stem cell medicine beyond the use of cell transplantation for tissue repair. It is our knowledge of stem cell biology that allows us to begin to understand some of the causes of this syndrome, as well as providing the means of preventing or repairing this damage."

This research provides the first demonstration that delayed CNS damage can be induced by a single chemotherapeutic agent and also generates the first animal model of such damage. These studies further demonstrate that this syndrome differs from that caused by irradiation and thus may represent a new class of delayed CNS degenerative damage.

• Men's Health News, Published: 2007 Dec 13

Extracts from fungi show potential as prostate cancer treatment

A new development in the fight against cancer: Recent research at the University of Haifa found that molecules found in common fungus Ganoderma lucidum aid in suppressing some of the mechanisms involved in the progression of prostate cancer.
The main action of the fungus: disrupting androgen receptor activity and impeding the proliferation of cancerous cells.

Over the past 3-4 decades much scientific research has dealt with the medicinal properties of different fungi. One of the important characteristics of fungi is the ability to fight cancer in a number of ways; however most of the research has been concentrated on how fungi affect the immune system. In this research, conducted by Dr. Ben-Zion Zaidman, under the direction of Prof. Eviatar Nevo and Prof. Solomon Wasser from the Institute of Evolution at the University of Haifa, and Dr. Jamal Mahajna from the Migal Galilee Technology Center, the researchers examined how fungi fight cancer from within cells. "Up to now, research has been based on enhancing the immune system with high-molecular-weight polysaccharides that act through specific receptors in cell membranes. We concentrated our research on low-molecular-weight secondary metabolites that can penetrate the cells and act at the molecular level from within the cell itself," explained Dr. Zaidman.

According to Dr. Zaidman, prostate cancer, one of the most common cancers found among men in the Western World, is controlled by the androgen receptor, especially at the initial stages of development of the disease. Therefore, all of the current medications used to treat prostate cancer work to reduce the production of androgens or to interfere with their function via the androgen receptor.

At the first stage of the research, 201 organic extracts from 68 types of fungi were produced with solvents such as ether, ethyl acetate and ethanol. These solvents are used to select molecules that are small enough to act from within the cells. Of the 201 extracts, 11 were found to deter androgen receptor activity by more than 40%. In further testing, 169 extracts were tested for cancer cell growth inhibition. In this study, 14 extracts were found to be active in inhibiting prostate cancer cells.

From among the active extracts, those from Ganoderma lucidum were found to be the most effective in inhibiting the function of the androgen receptor and controlling vital development of cancerous cells. "The results of this research are particularly interesting from a commercial aspect. Potential possibilities exist to establish research and development of bioactive metabolites from Ganoderma lucidum that could yield an anti-prostate cancer drug," remarked Dr. Zaidman.

• The science journal Nature, Published: 2007 Nov 19

Body's Immune System Can Keep Tumour Dormant

US scientists, studying genetically engineered mice to develop medicine for cancer, have reported this finding. They found that the body's immune system keeps tumors dormant for many years.

It also kills off some cancer cells, but not quickly enough to shrink or destroy the tumour, reported the online edition of Daily Mail.

The finding was described by the medical experts as "startling" and could lead to treatments that would allow patients to live with "neutralised" cancer for the rest of their lives.

Doctors have known for long that cancer can lie dormant in the body for years before suddenly coming back to life. They were however not aware exactly how they could be kept in check.

The findings are a result of a study led by Professor Robert Schreiber at the Washington University School of Medicine and published Monday in the online version of the science journal Nature.

"Thanks to the animal model we have developed, scientists can now reproduce this condition of tumour dormancy in the laboratory and look directly at cancer cells being held in check by the immune system," Schreiber said.

"Further research and clinical validation of this process may also turn established cancer into a chronic condition, similar to other serious diseases that are controlled long-term by taking a medicine," the scientist said.

• Medical Research News, Published: 2007 Oct 31

The next cancer drug might come straight from the grocery store, according to new research published in the November 2007 issue of The FASEB Journal.

In the study, French scientists describe how high and low doses of polyphenols have different effects. Most notably, they found that very high doses of antioxidant polyphenols shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Polyphenols are commonly found in red wine, fruits, vegetables, and green tea.

At relatively low doses, the French researchers found that the same polyphenols play a beneficial role for those with diseased hearts and circulatory systems by facilitating blood vessel growth. The amount of polyphenols necessary for this effect was found to be the equivalent of only one glass of red wine per day or simply sticking to a healthy diet of fruits and vegetables containing polyphenols. This diet is known as the "Mediterranean Diet." This study also adds to a growing body of research showing dose-dependent relationships for many types of commonly used compounds. For instance, research published in the October 2006 issue of The FASEB Journal shows that aspirin, through different mechanisms, also has a dose-dependent relationship for heart disease and cancer.

"When it comes to finding treatments for complex diseases, the answers are sometimes right there waiting to be discovered in unexpected places like the produce aisles and wine racks of the nearest store," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "But it takes modern science to isolate the pure compound, test it in the lab, and to go on from there to find new agents to fight disease."

According to the authors, the amount of polyphenols necessary to obtain an anti-cancer effect is the equivalent of drinking about a bottle of red wine each day. This amount of daily alcohol consumption obviously is unhealthy, but the research suggests that polyphenols extracted from plants or red wine could be converted into a pill that is highly likely to be safe. Such a pill also would be relatively easy and inexpensive to create and deliver.

"The use of plant polyphenols as therapeutic tools presents important advantages," said Daniel Henrion, senior author of the study, "because they have a good safety profile, a low cost and they can be obtained everywhere on the planet."

• Medical Research News, Published: 2007 Sept 19

Liver cancer marker could yield blood test for early detection

In the face of an emerging liver cancer crisis in Asia, researchers at the Chinese University of Hong Kong have developed a test that could help millions.
Due to widespread hepatitis B virus (HBV) infection, nearly 10 percent of China's population is at high risk for hepatocellular carcinoma (HCC), a liver cancer with low survival rates if not detected and treated early. Researchers report on a new blood screening technique that could make it possible to detect early-stage liver cancer and predict how well a patient will do following treatment. They present their data today at the American Association for Cancer Research's Second International Conference on Molecular Diagnostics in Cancer Therapeutic Development, in Atlanta, Georgia.

According to their report, the Chinese team has detected an altered version of RASSF1A, a tumor suppressing gene, in the blood of HCC patients and in 58 percent of HBV-infected test subjects. Healthy subjects showed no signs of the altered gene. They also found that patients treated for HCC with high blood levels of the gene were more likely to have a relapse of the disease.

"A large portion of the population throughout Hong Kong and China are carriers of hepatitis B, so many people are at risk for hepatocellular carcinoma," said K.C. Allen Chan, MBBS a professor at the Chinese University of Hong Kong. "And we hope that this will form the basis of an effective clinical test for early detection of hepatocellular carcinoma."

Hepatocellular carcinoma is one of the deadliest forms of cancer in China and throughout Asia, according to the researchers. In the West, liver cancer is usually a secondary cancer, caused by the spread of tumor cells from elsewhere in the body. In China, however, liver cancer mainly manifests as HCC, a primary cancer, which has been linked to hepatitis B and C infection and cirrhosis. Noticeable symptoms do not usually appear until the cancer has progressed, so it is rarely caught early, when intervention would be most effective, and survival rates are typically low, said Chan.

Currently, ultrasound and CT scans are the gold standard for detecting HCC. However, they are too expensive to be an effective mass screening tool, the researchers said. About 70 percent of patients exhibit a detectable increase in bloodstream amounts of alphafetoprotein, but a screen for this protein would miss many potential patients. "We need a new biomarker for hepatocellular carcinoma, something that can be used to screen large populations of at-risk people for follow-up studies," Chan said.

RASSF1A is a good candidate, according to Chan. Researchers have known that the DNA of HCC tumor cells lack a functioning copy of RASSF1A. In these cells, RASSF1A is "hypermethylated," meaning the RASSF1A gene has been physically altered by cancer-related processes that added clusters of carbon and hydrogen atoms, called methyl groups, to portions of the DNA within the gene. Hypermethylation is epigenetic - the gene is altered by environmental circumstances and is not inherited. Since the cell's protein making system can't access the gene, hypermethylation effectively knocks out the tumor-suppressing RASSF1A gene, which is then unable to stop cells from becoming cancerous.

While hypermethylated RASSF1A would make a useful biomarker for HCC, methylation-specific PCR - the polymerase chain reaction used to specifically amplify and detect methylated DNA - destroys about 85 to 93 percent of the DNA in a blood sample. Together with the fact that tumoral DNA is only present at very low concentrations in blood during early stages of HCC, this method has not been sensitive enough to detected altered RASSF1A in blood for the purpose of early cancer detection, Chan said.

To compensate, Chan and his colleagues invented a new technique that they call "methylation-sensitive enzyme-mediated real-time PCR," which combines real-time PCR, a technique that enables researchers to simultaneously detect and amplify a given gene, with an enzyme that breaks unmethylated DNA apart. With this new technique, Chan's team was able to separate out the altered methylated DNA, thus developing a more sensitive technique for detecting and quantifying hypermethylated RASSF1A derived from cancer cells in blood.

To test the relationship between altered RASSF1A and HCC - as well as test the new detection technique -- Chan and his colleagues conducted two studies involving HCC patients. In the first, they matched 63 pairs of patients, one with HCC and the other a chronic HBV carrier by age and sex, along with 30 healthy volunteers. They detected hypermethylated RASSF1A in 93 percent of the HCC patients, 58 percent of the HBV carriers and none of the healthy patients. The median RASSF1A levels for the HCC patients were 770 copies per milliliter and 118 copies per milliliter for HBV carriers.

"The respective levels of the gene for HCC patients and HBV carriers, is consistent with what we already know about the progression of the disease," Chan said. "The gene is altered very early in the procession of malignant transformation, and so we can see that the levels of the altered gene increase as the cancer process progresses."

In the second study, the researchers looked at 22 pairs of sex- and age-matched patients who had been enrolled in a HCC surveillance program involving 1018 HBV carriers. For the 22 HBV carriers who subsequently developed HCC, there was a significant increase in circulating RASSF1A levels from the time of enrollment to the time of cancer diagnosis. On the contrary, there was no significant change in RASSF1A levels over the same period for the 22 matched subjects enrolled in the same program who didn't develop HCC.

"As we refine the process of detecting hypermethylated RASSF1A, we hope to have a functioning test for hepatocellular carcinoma," Chan said. "A significant number of people will develop this cancer and it is only through early screening and detection that we can hope to help them."

• Devices/Technology, Published: 2007 Sept 5

Laser technology detects cancer by scanning surface veins

A new technology for cancer detection that eliminates the need for drawing blood has been developed by Purdue University researchers.

Researchers from Purdue's Cancer Center, Department of Chemistry and Weldon School of Biomedical Engineering collaborated with cancer and biotechnology experts from the Mayo Clinic to develop technology to detect tumor cells within the human body. By shining a laser on surface veins, such as those on the wrist and inside the cheek, researchers are able to reveal and count circulating tumor cells.

In addition to being less invasive, the new detection method is able to evaluate a much larger volume of blood than what can be drawn from a patient for analysis, said Philip Low, Purdue's Ralph C. Corley Distinguished Professor of Chemistry.

"In the initial stages of cancer, there are very few circulating tumor cells - cells that indicate the spread of cancer and initiate secondary tumor formation," Low said. "By increasing the volume of blood analyzed, we improve the sensitivity of the test and allow for earlier diagnosis. If there are two cancer cells in every 50 milliliters of blood, odds are the cells would not be found in a 10-milliliter blood sample. However, the cells would be found in the 100 milliliters of blood that flow through large veins each minute."

Optical imaging provides high resolution and chemical specificity for cancer detection, but it usually suffers from limited penetration depth, making it hard to reach tumors inside the body, said Ji-Xin Cheng, an assistant professor of chemistry and biomedical engineering.

"In vivo detection of circulating tumor cells in surface veins provides an excellent way to overcome this problem," Cheng said.

"Circulating tumor cells provide a benchmark for disease progression and precise monitoring of their levels could lead to personalized treatment," Low said. "This technique allows us to quantify the amount of circulating tumor cells present, as opposed to tests that provide a 'positive' or 'negative' result.

"Through such precise monitoring, a physician could evaluate the response to chemotherapy and regularly adjust the dosage so that only the exact amount needed would be administered. This could reduce the time a patient is treated and the serious side effects that occur."

The technique could provide doctors and patients results in a matter of minutes and save the medical industry millions of dollars in testing equipment, said Wei He, a graduate student in the Department of Chemistry and the Department of Biomedical Engineering. He worked on the project with Low and Cheng.

By directly labeling tumor cells while they are in the bloodstream, some of the costs and problems associated with testing drawn blood samples can be avoided, He said.

"One sample can require five to 10 test tubes during the course of sampling, processing and analysis such as handling, labeling and washing," He said. "In addition, large hospitals can have more than 300 cancer patients in one day. Such a large influx can cause delays in sample processing and delays can affect the results of analysis."

A paper detailing the technology and detection technique was published in the July 10 Proceedings of the National Academy of Sciences. In addition to Low, He and Cheng, postdoctoral researcher Haifeng Wang and Lynn C. Hartmann, a professor of oncology and associate director for education of the Mayo Clinic Cancer Center, co-authored the paper.

The technique uses a fluorescent tumor-specific probe that labels tumor cells in circulation. When hit by a laser, which scans across the diameter of the blood vessel 1,000 times per second, the tumor cells glow and become visible. The in vivo flow detection was performed on a two-photon fluorescence microscope in Cheng's lab. The researchers compared several methods and found two-photon fluorescence provides the best signal to background ratio. The technology is able to scan every cell that is pumped through the vessel, He said.

Low's team has developed two labeling agents that attach to different forms of cancer. One label targets ovarian, non-small lung, kidney and endometrial cancer, and the other targets prostate cancer.

These labels would be administered through an injection. The first label has already been tested in humans and has no adverse side effects and could potentially be administered weekly, He said.

Computed tomography, or CT, scans and magnetic resonance imaging, or MRI, are the current methods used to track the spread of cancer. These methods have a limited resolution, and a 1 millimeter tumor could go undetected by CT or MRI. The Purdue-developed technology can achieve single-cell resolution and can detect rare cell populations.

"Our method can detect cancer cells early in disease development and the test can be conducted frequently," Low said. "Discovering the cancer early and knowing whether it has metastasized, or spread, greatly improves a patient's chance for successful treatment."

The laser penetrates to a depth of 100 microns and is able to examine shallow blood vessels near the surface of the skin. Advanced optical technology could be incorporated into the technology platform and enable the method to reach deeper vessels that handle larger volumes of blood, Cheng said.

The Purdue team continues to work with the Mayo Clinic and is planning to initiate a clinical trial to further evaluate the technique. The team also plans to develop labels for additional types of cancer and to downsize the equipment to make the technology portable.

• Medical Research News, Published: 2007 Sept 13

In the September issue of Molecular & Cellular Proteomics, scientists describe a new technique that can detect how proteins undergo changes inside a cell.
The technique promises to improve our understanding of how proteins inside cells work and identify how some proteins are not modified properly in common diseases such as cancer and cardiovascular diseases.

In 2006, Ola Soderberg and colleagues established a technique called in situ proximity ligation assay (in situ PLA) to reveal protein-protein interactions in cells. The technique recognizes a target protein by binding a "probe" consisting of a pair of proteins attached to DNA onto the target protein. Then the DNA is replicated, producing a molecule that can be visualized under a microscope as a fluorescent spot - thus marking the presence of individual molecules in the target protein.

In the new study, Soderberg and colleagues developed a generalized version of the technique in which different probes can identify proteins that have undergone various changes in their structure. The researchers used this technique to detect a protein on the membrane of cells called platelet-derived growth factor receptor beta, which undergoes changes that will promote cell proliferation and movement. The technique is more sensitive and selective than other currently-used techniques, that is, it does not miss as many proteins as the other techniques do and the rate of mix-ups among the detected proteins is lower.

Article: " In Situ Detection of Phosphorylated Platelet-derived Growth Factor Receptor Beta Using a Generalized Proximity Ligation Method," by Malin Jarvius, Janna Paulsson, Irene Weibrecht, Karl-Johan Leuchowius, Ann-Catrin Andersson, Carolina Wahlby, Mats Gullberg, Johan Botling, Tobias Sjoblom, Boyka Markova, Arne Ostman, Ulf Landegren, and Ola Soderberg

The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.

• Cancer News, Published: 2007 August 7

Scientist identified Lung tumor suppressor

 

The gene is found in almost a quarter of all human lung cancers and in mice its mutation results in aggressive tumors that are more likely to spread throughout the body.
The study was conducted by a team of researchers led by Dr. Norman Sharpless at the University of North Carolina at Chapel Hill School of Medicine and Harvard Medical School.
As part of the study researchers developed a mouse model with defects in the LKB1 gene that causes one of the most lethal malignancies in man, a form of lung cancer called squamous cell carcinoma.
The researcher demonstrated that cancer developed at a much faster rate in genetically engineered mice as compared to those with defects in other tumor suppressors commonly mutated in lung cancer.
The study found that these mice exhibited not just one, but all three forms of non-small cell lung cancer, adenocarcinomas, squamous cell carcinomas and large cell carcinomas and they were more likely to metastasize, or spread to other organs.
"Clearly mice with lung cancers harboring LKB1 mutations do much worse than those with other types of cancers; however, we still do not know what this gene does," Nature quoted Sharpless, as saying.
Researchers then analyzed DNA from 144 non-small cell lung cancer patients to study whether the mouse model related to genetic events of human lung cancer.
The study noted defects in LKB1 in 34 percent of human lung adenocarcinomas, 19 percent of squamous cell carcinomas and 10 percent of large cell carcinomas.
Dr. Neil Hayes, co-author of the study explained that by studying cancer progression in patients, specific LKB1 mutations can be identified.
"Based on this study and ones like it we should be able to sort patients into groups based on exactly what genetic lesion is causing their cancer," Hayes said.

• Cancer News, Published: 2007 July 27

Researchers at the University of Michigan have identified a gene linked to the development of an aggressive form of breast cancer. The researchers found that the gene, FOXP3, suppresses tumor growth. FOXP3 is located on the X chromosome, which means a single mutation can effectively silence the gene. This is unusual, as only one other gene linked to cancer has been found on the X chromosome. When one copy of the FOXP3 gene is silenced, the researchers found in studying mice, 90 percent of the mice spontaneously developed cancerous tumors. The researchers also looked at FOXP3 in human breast tissue cells, comparing cancerous and non-cancerous cells. FOXP3 was found to be either deleted or mutated in a substantial portion of the cancer sample: about 80 percent of the cancer tissues studied did not express the gene at all.

In addition, the researchers found FOXP3 to be a repressor of HER-2, a protein that typically marks a more aggressive form of breast cancer. The researchers believe FOXP3 suppresses the HER-2 gene. HER-2 can be activated by many different factors, but the researchers found that when FOXP3 is normal, it keeps HER-2 levels low; when FOXP3 is missing or mutated, HER-2 levels are likely to rise.

The researchers have shown that FOXP3 was reduced or missing in about 80 percent of the more than 600 cases of breast cancer tissue examined. At this point, the researchers do not know if FOXP3 can predict breast cancer risk, like the BRCA1 and BRCA2 genes, both of which are linked to a higher risk of breast cancer.

 

“FOXP3 defects promote cancer development. We do not know whether this is a genetic defect that puts women at higher risk. For treatment, this gene could be quite important, but for diagnosis, it’s too early to tell,” says study author Yang Liu, Ph.D., deNancrede Professor of Surgery at the U-M Medical School and co-director of the cancer immunology program at the U-M Comprehensive Cancer Center. Results of the study appear in the journal Cell.

 

Initially, the researchers were studying FOXP3’s role in autoimmune disease, when they noticed that female mice with one copy of the mutated form of the gene were developing breast cancer. Moreover, the tumors expressed high levels of ErbB2, the mouse equivalent of HER-2. Breast cancer is rare in mice, and ErbB2-positive breast cancer is even more rare.

“FOXP3 is the first X chromosome-linked gene that suppresses breast cancer and represses the HER-2/ErbB2 oncogene. Given the significant role HER-2 plays in breast cancer and the widespread defects we found on FOXP3, it is likely that this gene play an important role in suppressing breast cancer,” says Pan Zheng, M.D., Ph.D., associate professor of surgery and pathology at the U-M Medical School.

• Medical Research News, Published: 2007 July 17

Experts in the United States say that eating the right food with certain medications could improve the effectiveness of drugs and also reduce the cost of treating patients.

The oncologists from the University of Chicago suggest that taking a breast cancer drug with fatty food, rather than on an empty stomach, boosts absorption of the drug and means patients could take lower doses, which would reduce costs.

They found that taking the breast cancer drug lapatinib at the same time as a fatty meal may make it work at least three times as well and when grapefruit juice accompanies the meal the researchers say the pills could be five times more effective than normal by aiding absorption.

The researchers say however that further tests are needed and that patients should not alter how they take their cancer drugs.

They suspect a better understanding of the relationship between common drugs such as statins and for example grapefruit juice could possibly cut down drug costs.

In the past experts have warned of the potential dangers of interactions between food and drugs which can render drugs becoming toxic, or less effective.

Professors Mark Ratain and Ezra Cohen say they have found that taking the breast cancer drug lapatinib (TYKERB) with food, rather than on an empty stomach as suggested on the label, increased the availability of the drug in the body by 167%, meaning the drug could work more effectively; taking it with a meal rich in fat boosted levels by 325%.

The researchers say their findings about the interactions between foods and anti-cancer drugs could be exploited to help decrease costs and increase the benefits from such drugs.

Professor Ratain says by simply changing the timing and taking lapatinib with a meal instead of on an empty stomach only 40% of the drug is needed.

Grapefruit is known to boost absorption of certain drugs and Professor Ratain says drinking grapefruit juice, which is known to increase the rate at which some drugs enter the blood stream could increase these savings even further.

Ratain also suggests that eating such "value meals" at the same time as taking drugs could have other benefits too; a major toxicity associated with lapatinib is diarrhoea, which is thought to be caused by some of the drug being unabsorbed, therefore taking lower doses with food to boost its absorption should help reduce this side-effects.

He says that one 250mg lapatinib pill accompanied by food and a glass of grapefruit juice may yield plasma concentrations comparable to five pills on an empty stomach.

The authors caution against patients experimenting themselves and say more research to assess the effects of drug-combinations on patients.

They are in fact currently conducting a study testing the effect of combining a drug with grapefruit juice.

The Medicines and Healthcare Products Regulatory Agency says any new recommendations about drug dosages need to be backed up by evidence and full testing through clinical trials.

The research is published in the Journal of Clinical Oncology.

• Men's Health News, Published: 2007 July 1

Lifestyle changes and prostate cancer

Up to 73% of men with prostate cancer take nonprescription supplements, and smaller numbers use diet, exercise, or both in the hope of improving their outcome.
Most of these men also receive conventional therapy, but a few depend on lifestyle alone. The appeal of lifestyle therapy is obvious-but does it work. Experts don't know, though research raises hope that it may have a beneficial impact, reports the July 2007 issue of Harvard Men's Health Watch .

All of the 93 men who signed up for the trial had newly diagnosed low- to moderate-grade cancers that were localized to the prostate gland. Half were randomly assigned to a lifestyle program, and half got no advice on lifestyle changes. The program that researchers created included four elements: An ultra-low-fat vegan diet; supplements, including soy, fish oil, vitamins E and C, and selenium; an exercise program of walking 30 minutes six days a week; and stress reduction that included yoga-based stretching, breathing, and meditation for an hour a day.

At the end of a year, a small but significant difference was evident. The average PSA in the intensive lifestyle group fell, whereas the average PSA in the untreated men rose. The participants in the lifestyle group also showed favorable cancer-fighting changes in their blood.

Much more research is needed before lifestyle therapy can be recommended clinically. But, the Harvard Men's Health Watch notes, men with prostate cancer may choose not to wait until science catches up with their disease. And since the lifestyle program studied is good for general health, its elements will make a reasonable addition to any prostate cancer program.

• Medical Condition News, Published: 2007 June 12

In a special publication sent to thousands of oncologists nationwide this month, University of Rochester Medical Center scientists offer an in-depth examination of cancer-related fatigue, with hope that a better understanding of the topic will prompt new research and treatment.

Virtually all cancer patients complain of some degree of persistent fatigue. Coping with this challenging side effect is critical to surviving cancer, especially since many people desire to work, raise children, run a household, or engage in recreation throughout their treatments, said Joseph Roscoe, Ph.D., a co-author and research associate professor of Oncology at the University's James P. Wilmot Cancer Center.

"It used to be that fatigue was viewed as an inevitable part of sickness," said Roscoe, a cancer survivor. "Now we know better, and there's a great deal of ongoing research about what causes fatigue and how it can be managed. For some people, fatigue is so debilitating that they want to stop their cancer treatments, which is why it is particularly important to find ways to address this problem."

During his own bout with cancer fatigue, Roscoe recalled feeling "jet lagged all the time." But rest or sleep does not alleviate cancer fatigue, and it often persists for months. In some studies, patients report more stress from fatigue than from pain, depression or nausea.

Unfortunately, no one has turned up a quick fix. "Exercise is looking very promising and one psychostimulant drug, modafinil, is being studied as a potential new treatment," Roscoe said. "But nothing yet has clearly demonstrated the ability to relieve cancer-related fatigue."

The Oncologist, a peer-reviewed journal, published a body of work from the James P. Wilmot Cancer Center's Behavior Medicine Unit on current knowledge of this condition. Six articles form a special journal supplement, which is intended for use as a physician reference guide.

The following is a snapshot of what is reviewed in the journal:

Scale of the problem. Of the 1.3 million Americans diagnosed with cancer in 2005, 95 percent of the people scheduled to receive chemotherapy or radiation expected to experience fatigue. Studies show the frequency of actual fatigue during chemo ranges from 70 to 100 percent; likewise, 90 percent of patients who receive radiation therapy report fatigue. Also, up to 40 percent of patients report unusual fatigue upon diagnosis, a sign that fatigue is an early symptom of malignancy as well as a consequence of treatment.

Underlying causes. Cancer fatigue disrupts several interrelated systems: physiological, biochemical, psychological. The effect varies among individuals and also during different phases of treatment. It likely involves changes in the endocrine system, circadian rhythms, metabolism, cytokines and seratonin production. Predisposing factors must be understood before researchers can develop useful prevention or treatment strategies.

Measurement of a subjective symptom. More than 20 different assessments are used to diagnose fatigue, from single-question scales to multidimensional measurements of a patient's physical, emotional and cognitive functioning. Most patients can easily rate their fatigue on a scale from 0 to 10, researchers said. However, it is important for physicians to distinguish cancer fatigue from other ailments such as depression, and treat accordingly.

Fatigue and cancer-related sleep disorders. Approximately 25 to 50 percent of all prescriptions that doctors write for cancer patients are for hypnotics. Studies show that sleep disturbances are more severe in the most fatigued patients, suggesting a reciprocal relationship between these two distinct conditions.

Drug remedies. The first step to managing cancer fatigue is to treat conditions that may contribute to it, such as anemia, pain or depression. Studies show that anemia medications alleviate cancer fatigue to some degree. Other classes of drugs called psychostimulants have shown promise in open-label trials. Further research is needed.

Non-drug remedies. A growing body of evidence shows that exercise and support groups help people with cancer fatigue the most. Additional studies into nutrition therapy, yoga, mindfulness stress reduction, and polarity therapy also show promise. Many people with cancer already use non-drug behavioral therapies on their own, researchers said, but it's important that the scientific community continue to fund and study these interventions.

• Medical Studies/Trials, Published: 2007 June 3

Women with breast cancer who receive higher doses of radiation with IMRT each day can reduce their treatment time by two weeks without increasing side effects, according to a study released in the June 1 issue of the International Journal of Radiation Oncology*Biology*Physics, the official journal of the American Society for Therapeutic Radiology and Oncology.

Intensity modulated radiation therapy (IMRT) is a specialized form of radiation therapy that allows the radiation to be more exactly shaped to fit the tumor. With IMRT, the radiation beam can be broken up into many "beamlets," and the intensity of each beamlet can be adjusted individually. In some cases, this may allow doctors to send a higher dose of radiation to the tumor, potentially increasing the chance of a cure.

In this particular study, IMRT was delivered with an additional concurrent "boost," or high-dose radiation to the lumpectomy site where the tumor was removed. The standard boost is typically given after the four to five weeks of conventional radiation therapy and adds another one to two weeks to the treatment time. The boost in this study was given during the four weeks of whole breast irradiation to see if the increased dose would increase side effects. Some women who receive standard radiation therapy for breast cancer develop skin irritation as a side effect from the radiation's effect. This side effect is similar to sunburn and usually heals on its own once treatment ends. Doctors believe that without the use of IMRT, the elevated level of radiation would not be tolerated by the patients.

Seventy-five women were treated in this Phase II study using IMRT for four weeks, as opposed to the traditional six to seven weeks. The women were treated with a slightly higher radiation dose to the entire breast while also delivering the boost to the original lumpectomy site of the breast. Though the dosage of radiation was increased, the daily treatments of radiation were at a well-tolerated level. Doctors graded the skin toxicity of each patient on a scale of Grade 0 (no skin toxicity present) to Grade 9 (severe toxicity). More than half of the women, 65 percent, had Grade 1 skin toxicity at the end of the four week treatment period, with 23 percent of the women reporting a skin toxicity of Grade 2. The other 12 percent had Grade 0 toxicity, meaning they showed no skin irritation. None of the patients had higher than Grade 3 toxicity.

In the short-term follow-up of six weeks, doctors found that the all toxicity levels had returned to normal, including the women who had Grade 2 skin toxicity.

This study demonstrated that in addition to safely increasing the daily dose to the whole breast during the four-week period, it is possible to deliver the "boost" concurrently, eliminating the extra two weeks and possibly sparing the women from more discomfort during the post-operative treatment.

"Earlier studies have proven without a doubt that six to seven weeks of radiation therapy after a lumpectomy cures most early-stage breast cancers. Now, we're working to find ways to make the treatments easier for patients by reducing side effects or shortening the treatment. This study presents a good foundation of knowledge for the potential of IMRT for breast cancer," said Gary Freedman, M.D., lead author of the study and a radiation oncologist at Fox Chase Cancer Center in Philadelphia. "With long-term follow up and further study, we can aim to condense the length of post-operative treatment for these women."

• Medical Research News, Published: 2007 May 24

Scientists have made a breakthrough in understanding how cancers spread in what could lead to new ways of beating the disease.

 
The University of Manchester study used embryonic stem (ES) cells to investigate how some tumours are able to migrate to other parts of the body, which makes the treatment of cancer much more difficult.

Dr Chris Ward, in the University's Faculty of Medical and Human Sciences, studied a crucial change that makes cancer cells able to start moving and spread into other tissues.

Normal cells, as well as early cancer cells, are called epithelial cells because they bind tightly to each other forming stable layers of tissue. However, as a tumour becomes more advanced, some of the cells change to become mesenchymal.

Mesenchymal cells do not bind to each other, forming more disorganised tissues in which the cells can move around. Since this crucial change known as the epithelial-mesenchymal transition, was first observed in the early embryo, Dr Ward theorised that embryonic stem cells might undergo a similar process.

Dr Ward, whose findings are published in the journal Molecular Biology of the Cell, said: "We have shown that ES cells spontaneously change in a manner that is remarkably similar to the epithelial-mesenchymal transition. They lose the proteins that cells use to bind to each other and have other protein alterations that are characteristic of spreading cancer cells.

"Since ES cells can be grown in the laboratory where they keep the characteristics of the cells in the early embryo they can be studied in detail. By studying these ES cells we have already identified a novel component of this transition process. We expect the use of ES cells will lead to the identification of other unknown factors involved in cancer cell spread, hopefully leading to new avenues for cancer therapy."

Previously, it has been quite difficult to study this crucial transition in cancer cells as it only happened to a limited number of cells in a growing tumour. The team's discovery that it happens spontaneously in ES cells means that it can be studied more easily in the laboratory.

"Understanding how cancer cells start to spread is tremendously important for cancer research; tumours that do not spread are rarely, if ever, dangerous," said Dr Ward, who leads the stem cell research group in the School of Dentistry.

"It is the ability of tumours to invade into other tissues and spread around the body that makes them so dangerous. Finding out more about the mechanism that controls the spread of cancer cells will help us find new treatments that can prevent tumours spreading and make them essentially harmless."

The study, which was funded by the Association for International Cancer Research (AICR) and also involved the University's Immunology Group at the Paterson Institute for Cancer Research (PICR), used embryonic stem cells to investigate how the protein E-cadherin stopped cells from migrating during normal growth.

The team found that, as well as helping cells stick together, E-cadherin also blocked the action of another protein known to increase the mobility of cells. This important dual function of E-cadherin opens up the potential for new targets to prevent tumours from spreading.

Derek Napier, Chief Executive of AICR, said: "Dr Ward's work will open the door to a detailed dissection of the process that makes cancers spread around the body.

"Scientific research occasionally makes sudden leaps forward when a new way of investigating something is discovered. We predict that this will lead to a huge growth in our understanding of cancer spread and the development on several new approaches to stopping it."

• Women's Health News, Published: 2007 May 6

Radiation for breast cancer not likely to increase heart attack risk

 

In 1973, two researchers published an article in the journal Lab Investigation saying that radiation to the breast area might damage the capillaries and restrict blood flow to the heart.

Since that time, conflicting reports about the long-term risk of radiation to the heart have been published. According to a study released today in the International Journal of Radiation Oncology* Biology*Physics , the official journal of ASTRO, elderly women who receive radiation therapy for early-stage breast cancer appear to have no increased risk of a heart attack after taking pre-existing cardiac risk factors into account. Interestingly, pre-existing cardiac risk factors such as diabetes, hypertension and hyperlipidemia do not potentiate the effects of radiation on the heart.

Using the Surveillance, Epidemiology and End-Results (SEER) database, researchers conducted a retrospective study of female Medicare recipients aged 65 and older who were diagnosed with breast cancer from 1992 to 2000. Researchers then reviewed the records of more than 48,000 breast cancer patients. Of those women, 19,897 had lumpectomies (42 percent) and 26,534 has mastectomies (55 percent). Of all the patients in the study, 21,502 (45 percent) received radiation therapy and 4,151 (9 percent) received both radiation and chemotherapy. Patients with pre-existing heart disease were less likely to receive radiation.

After adjusting for pre-existing heart problems as well as other health and socioeconomic factors like age, race, marital status, income, rural versus urban living and receipt of chemotherapy, doctors found that women who received radiation were not at an increased risk of having heart attacks. As would be expected, heart attacks were more likely to be found among individuals already at higher risk for heart disease, such as women of increased age, African-American ethnicity and those with more co-morbid conditions.

"Women with breast cancer are naturally concerned about the side effects of their treatments, including radiation therapy. This study provides them and their physicians with some peace of mind knowing that the benefits of radiation appear to outweigh the cardiac risks," said John Doyle, Dr.P.H., the lead author on the study and an Adjunct Assistant Professor of Health Policy and Management and Epidemiology at the Mailman School of Public Health of Columbia University in New York.

• Medical Studies/Trials, Published: 2007 April 30

The American Cancer Society is launching a major new cancer research study that may be the 'last best chance' to do large-scale population research in the United States to discover the genetic and environmental factors that cause and prevent cancer.

The Cancer Prevention Study 3 (CPS-3) aims to enroll a geographically and ethnically diverse group of half a million adults across the United States to help pave the way for the next generation of American Cancer Society research and further advance the understanding of the lifestyle, environmental, and genetic factors that cause or prevent cancer. It is the latest in a series of important large-scale American Cancer Society studies stretching back to the 1950's that have contributed significantly to the understanding of how tobacco, obesity, diet, physical activity, hormone use, air pollution, and other factors affect the risk of cancer and other diseases.

"There are no U.S. studies on the horizon positioned to take advantage of rapidly developing new knowledge and technologies over the coming decades, except CPS-3," said Eugenia E. Calle, PhD, managing director of analytic epidemiology at the American Cancer Society, who is leading the study. "This type of study involves hundreds of thousands of people, with diverse backgrounds, followed for many years, with collection of biological specimens and assessments of dietary, lifestyle and environmental exposures. It also requires active follow-up to discover if and when study participants develop cancer."

Large studies of up to one million participants are being conducted in Europe, the United Kingdom, China, Taiwan, and even Estonia. Unlike the U.S., in many other countries, health care is administered through a national system that gives each citizen a unique identification number linking health care data and all visits to government clinics. In addition, electronic registries of disease can often be linked to study members. "Another important factor is the fact that people in other countries are often willing to be enrolled in a study, historically a serious challenge in the U.S.," said Dr. Calle.

Enrollment in CPS-3 will take place at 64 of the 4,800 Relay For Life, events taking place across the U.S. in 2007, and continue at select Relay events through 2011 (a pilot program enrolled participants at a handful of Relay events in 2006). Relay For Life is a fun-filled overnight event designed to celebrate survivorship and raise money for research and programs of the American Cancer Society. During the event, teams of people gather at schools, fairgrounds, or parks and take turns walking or running laps. Each team tries to keep at least one team member on the track at all times.

CPS-3 will enroll men and women between the ages of 30 and 65 who have never been diagnosed with cancer (important in studies that focus on the causes of cancer), and who are willing to make a long-term commitment to the study. Enrollees spend 20 to 30 minutes at a Relay For Life event, where after consenting to participate they complete a brief study questionnaire, get a simple waist measurement, and provide a small blood sample (similar to a doctor's visit).

For the next 20 or more years, Society researchers will track CPS-3 participants through questionnaires mailed every few years, identifying and studying factors associated with cancer occurrence or prevention in the study cohort.

Researchers will use the data from CPS-3 to build on evidence from a series of American Cancer Society studies that began in the 1950s and involved hundreds of thousands of volunteer participants. The Hammond-Horn study and the first Cancer Prevention Studies (CPS-I and CPS-II) have played a major role in understanding cancer prevention and risk, and have contributed significantly to the scientific literature and to the development of public health guidelines and recommendations. Those studies confirmed the link between cigarette smoking and lung cancer, showed that obesity increases the risk of several cancers, and linked aspirin use to a lower death rate from colon cancer. The current study, CPS-II, began in 1982 and is still ongoing. But changes in lifestyle and in the understanding of cancer in the more than two decades since its launch make it important to begin a new cohort.

"It is not an exaggeration to say the American Cancer Society is the only organization likely to be able to successfully recruit and retain such a large-scale population for cancer research," said Dr. Calle. "We have an excellent record dating back to the 1950's of conducting these types of studies; we can bring together a world-class research department with a unique community-based volunteer structure like Relay For Life; we can reach diverse populations nationwide who have a shared commitment to cancer research and to eliminating this disease; and because we are a non-profit organization with the ability to partner with volunteers, we can conduct the study for much less than would be possible for the government or a private corporation."

"While science can do a lot to explain the biology and genetics of cancer, some of the most valuable information we have is a direct result of the contributions of dedicated individuals over several generations," said Dr. Calle. "We are once again looking to the dedication, compassion, and generosity of Americans to come through and help us provide answers that we know will save lives and improve the outlook for future generations."

• Medical Studies/Trials, Published: 2007 April 12

Cancer occurs more frequently in the prostates of men than in any organ other than the skin. While DNA damage caused by exposure to the sun is likely the cause of many skin cancers, the cause of prostate cancer remains largely unknown.

Research conducted by the group of Marikki Laiho, M.D., Ph.D., a Professor at the University of Helsinki, Finland, in collaboration with Donna Peehl, Ph.D., an Associate Professor (Research) at Stanford University, US, points to absence of critical mechanisms protecting prostate cells from DNA damage as a key contributor to the development of prostate cancer.

Results of the study will be published in the online Early Edition of the Proceedings of the National Academy of Sciences, USA, during the week of April 9-13.

The investigators used primary cultures of normal epithelial cells derived from patients' surgical specimens to examine responses to DNA damage induced by irradiation or chemicals. These cultured cells are the "progenitor" cells in the prostate in which cancer may originate, and therefore provide a realistic experimental model in which to study carcinogenic processes.

After exposure to DNA damaging agents, cells typically mount several types of defensive mechanisms to allow repair of DNA damage prior to cell division. These mechanisms prevent the passage of damaged genetic material to daughter cells, which would contribute to the conversion of those damaged cells to cancer. One of these protective mechanisms is cell cycle checkpoint arrest, which is mediated by a series of molecular events triggered by DNA damage.

Surprisingly, normal prostate cells were unable to enforce cell cycle checkpoint arrest and continued to proliferate following DNA damage. Early events involving cellular recognition of DNA damage were intact, so lack of checkpoint arrest in these cells was not due to inability to recognize DNA damage. Rather, inability to enforce cell cycle arrest was linked to low levels of the protein Wee1A, a tyrosine kinase that phosphorylates and inhibits cyclin dependent kinase 2 (cdk2). In the absence of Wee1A activity, cdk2 remained active and continued to drive the prostate cells to undergo cell division. In conjunction, slower clearance of DNA damage foci suggested persistent DNA damage. When Wee1A protein was restored in these cells, checkpoint control was rescued, showing that Wee1A was indeed critical to this important pathway.

When using cultured cells, there is always a concern that the in vitro environment may alter cellular behavior. To confirm that the observed results were not an artifact of cell culture, the investigators used a novel model system of "tissue slice cultures", developed by Peehl. Cores of fresh tissue were bored from surgical specimens, then were precision-cut to thicknesses of only a few hundred microns. These slices were incubated and retained their structure and function for several days. The value of tissue slice cultures is that all elements of the whole tissue remain intact, permitting realistic experiments that are not feasible to perform directly in humans. The responses to DNA damage of the normal epithelial cells in these tissues were similar to those of the cell cultures, signifying that defensive mechanisms against DNA damage are indeed lacking in the human prostate.

The lack of Wee1A-mediated DNA damage-induced checkpoint enforcement is not the only defective protective mechanism in prostate cells. In 1995, Peehl in collaboration with another investigator at Stanford, Amato Giaccia, Ph.D., reported in Cancer Research that normal prostatic epithelial cells lacked the p53 response to DNA damage. The p53 protein is a major tumor suppressor and lack of p53 function leads to genomic instability and malignancy. The defects in the two checkpoint enforcement pathways, mediated by p53 in one and by Wee1A in the other, are unrelated, since correcting the Wee1A pathway did not restore p53 function in prostate cells.

The use of human cells and tissues in these studies was key to the medical relevance of the findings. The human prostate is almost unique among mammals in having a high incidence of prostate cancer. Rodents, most commonly used in the laboratory to study mechanisms of cancer, do not develop prostate cancer spontaneously. The absence of at least two key checkpoint elements in the DNA damage response pathways may predispose human prostatic epithelial cells to accrual of DNA lesions and provide a mechanistic basis for the high incidence of cancer in the prostate.

Why prostate cells lack these mechanisms is unknown, but discovery of ways to restore these checkpoints controls might protect against prostate cancer.

The study was funded by the Department of Defense Prostate Cancer Research Program, the Academy of Finland, Biocentrum Helsinki, the Finnish Cancer Organizations and the Finnish Cultural Foundation.

• Medical Studies/Trials, Published: 2007 Mar 22

When Susan Wright learned that she had a type of fatal, rapidly growing brain cancer at age 46, her doctors at the University of Florida told her she wouldn't live more than 18 months.

Three years later, Wright is still alive, rides her bike and spends days canoeing on a local river. "I can't do things at the level that I used to, but I'm still here," she said.

Wright and her doctors attribute her survival in part to a new vaccine, developed by a researcher at the Stanford University School of Medicine, to treat her aggressive brain tumor called glioblastoma. Although her doctors in Florida didn't have access to the vaccine, they sent Wright to Duke University where she spent the next year receiving the experimental treatment in a clinical trial.

"I remember that as a time of great health and optimism," she said. However, Wright has not been cured, and has since had a relapse and is on chemotherapy. But even with the relapse, the vaccine has helped Wright lived longer than most glioblastoma patients, who have an average survival rate of less than a year.

Now the vaccine will be tested at Stanford as well as other sites nationwide. Originally developed by Albert Wong, MD, professor of neurosurgery and member of the Stanford Comprehensive Cancer Center, results so far have been promising enough to spur a 20-center trial sponsored by Celldex, the New Jersey-based company developing the therapy. Wong has stock in Celldex and is a consultant for the company.

The vaccine is already attracting interest, and is scheduled to be featured during the March 22 "CBS Evening News" broadcast in a report by anchor Katie Couric.

Stanford expects to begin enrolling patients in the trial in April. For Wong, the start of this trial is the result of a career-long interest in the vaccine and in curing glioblastoma. "When you hear about people being diagnosed with brain cancer and dying several months later, that's usually glioblastoma," he said. Any treatment that improves survival time in people with the disease is a significant improvement, he said.

Only 3 percent of people with glioblastoma survive five years, with the average survival being just under a year. The disease resists treatment with chemotherapy and radiation, and spreads so effectively throughout the brain that a surgeon can no more remove every last cell than a picky eater could remove every bit of cheese from a casserole.

The vaccine arose from a 1992 discovery Wong made while he was a postdoctoral fellow at Johns Hopkins University. He found that in many glioblastomas the cells are dotted with an unusual form of a common protein called epidermal growth factor receptor, or EGFR. Although the gene for that altered protein doesn't contain any mutations, the cells inexplicably chop out several chunks of the normal protein before lodging it on their cell surface. He named this unusual variant EGFRvIII because it was the third variant he had discovered.

Anything that makes a tumor cell look different from the surrounding tissue intrigues researchers hoping to develop cures. In this case, Wong thought he could direct the immune system to attack cells carrying EGFRvIII by administering a vaccine. The activated immune cells resulting from the vaccine would ignore normal versions of EGFR on other noncancerous cells throughout the body, attacking only the cancer.

In later work, Wong realized that other solid tumors - such as those in the lung, prostate and ovary - also sport EGFRvIII. This made him think that a vaccine that attacks the unusual protein might be widely useful in treating these tumors.
In mice, the vaccine worked exactly as Wong had hoped. Based on that success, colleagues at the University of Washington started a small phase-1 trial to test the vaccine in patients with ovarian and prostate cancers that contain EGFRvIII. Each of those patients showed a response to the vaccine, but so far not enough time has elapsed to know whether it prolonged their lives.

Wong's colleagues at Duke University started another small phase-1 trial, this time testing the vaccine in people with glioblastoma. In that trial, 14 patients who got the vaccine lived on average more than 21 months. That's still not considered a cure, but it's a significant improvement over the typical survival rate.

In a follow-up phase-2 trial of 23 patients in which Duke researchers partnered with colleagues at M.D. Anderson Cancer Center, the average survival went up to about 30 months because of some changes in how the doctors delivered the vaccine and in the types of patients selected to receive it. The previous trial had accepted all glioblastoma patients, whereas this one only accepted patients whose tumors made EGFRvIII. That was the trial in which Wright participated. Results from both trials will be published in the next year.

The phase-2 trial opening up at Stanford will include 81 patients-the largest trial of the vaccine to date. Like the previous phase-2 trial, this one will only enroll patients whose tumors produce the altered protein.

For her part, Wright hopes those people experience the same tumor response and good health she felt while on the vaccine. "It's the only treatment I've had where I felt no side effects," Wright said. "It was really a wonderful experience."

• Miscellaneous News, Published: 2007 Mar 25

The Food and Drug Administration (FDA) is re-issuing its warning to consumers not to drink "Jermuk" brand mineral water due to the risk of exposure to arsenic, a toxic substance and a known cause of cancer in humans.
The agency is providing this information again to consumers due to an expansion of the recall initiated by the products' importers and distributors. "Jermuk" water is imported from Armenia and distributed under different labels in California. Five brands of these products have been recalled since March 7.

The latest recall, which was initiated on March 16 by the product's distributor, Andreas Andreasyan DBA Arnaz & Nelli Co., North Hollywood, CA., is for "Jermuk Natural Mineral Water Fortified with Gas from the Spring". This product is additionally labeled as "Produced by Sam-Har Co. Republic of Armenia" and "Exclusive Distributor in USA: Arnaz & Nelli Inc., CA 91605".

Although arsenic is a well known human poison, there is little chance that someone would become seriously ill after consuming the recalled products over a brief period of time (days to weeks). However, it is likely that the person would experience nausea, abdominal pain and possibly vomiting, which are indicators of arsenic toxicity.

FDA has sampled the contents of 500 milliliter (mL) green glass and/or plastic bottles of all of these brands and found they contained 454-674 micrograms of arsenic per liter of water. FDA's standard of quality for bottled water allows no more than 10 micrograms per liter.

The agency is investigating whether other bottle sizes or types of packaging contain similarly tainted products, and will continue working to remove all such bottled water from the market.

There have been no illnesses reported at this time. Consumers who drank this water and have concerns are encouraged to contact their health care provider.

FDA may provide additional updates as more information becomes available.

The following products were recalled on March 7:

"Jermuk Original Sparkling Natural Mineral Water Fortified With Natural Gas From The Spring". The product is in glass bottles and is additionally labeled as "2006 Jermuk Mayr Gortsaran CJSC" and "Imported by: Zetlian Bakery Inc." The importer and distributor is Zetlian Bakery, Inc., Pico Rivera, CA.
"JERMUK,1951, NATURAL MINERAL WATER, JERMUK MAYR GORTSARAN CJSC." The product is in plastic bottles which are additionally labeled as "Imported by: Zetlian Bakery Inc." The importer and distributor is Zetlian Bakery, Inc., Pico Rivera, CA.
"Jermuk Sodium Calcium Bicarbonate and Sulphate Mineral Water". The product is additionally labeled as "Bottled by ARPI Plant, Republic of Armenia" and "Exclusive US importer and distributor: Importers Direct Wholesale Co., Los Angeles, CA". The product is being recalled by Importers Direct Wholesale Company, Los Angeles, CA.
"Jermuk, Natural Mineral Water Sparkling". The product, recalled on March 7 is additionally labeled as "Bottled by Jermuk Group CJSC" and "Sale Agent Kradjian Importing Co. Inc." in Glendale, CA. The product is being recalled by Kradjian Importing Company, Glendale, CA.

• Men's Health News, Published: 2007 Mar 11

After being diagnosed with aggressive prostate cancer, many men are told that their disease is untreatable and that less aggressive treatment is best.

Often this means patients are told to watch and wait -- that is, to do nothing at all. A new study by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center turns conventional wisdom on its head, finding either surgical removal of the prostate (prostatectomy) or radiation treatment more than doubles the life expectancy for these patients when compared with those receiving the conservative approach.

Patients with the most aggressive non-metastatic prostate cancers (Gleason scores 8-10), if treated with prostatectomy or radiation, can expect to live more than 14 years; those treated conservatively will live, on average, less than 7 years. The study appears in the March Journal of Urology.

"Unfortunately, pessimism abounds among many doctors, who believe that aggressive prostate cancers are beyond cure and should only be followed with watchful waiting, forestalling any immediate treatment. This new study points to the fallacy of this outlook, finding surgery and radiation more than double the life expectancy for these patients," says Dr. Ashutosh Tewari, the study's first author and director of robotic prostatectomy and urologic oncology outcomes at NewYork-Presbyterian/Weill Cornell and the Ronald P. Lynch Associate Professor of Urologic Oncology at Weill Cornell Medical College.

The study involved a retrospective statistical analysis of outcomes of 453 cases of clinically localized aggressive prostate (graded Gleason scores 8-10) at the Henry Ford Health System in Detroit.

"Ultimately, randomized clinical trials studying long-term outcomes will be necessary to fully demonstrate the benefits of treatment for these patients," adds Dr. David Nanus, a study co-author and medical director of the Genitourinary Oncology Program at NewYork-Presbyterian/Weill Cornell. He is co-division chief of hematology and medical oncology and the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine at Weill Cornell Medical College.

The study's senior author is Dr. Mani Menon of the Henry Ford Health System in Detroit.

In 2006, roughly 234,000 American men were diagnosed with prostate cancer. The most aggressive prostate cancers often result in early metastasis and death. Left untreated, as many as 85 percent of men die from prostate cancer within 10 years of diagnosis. High-grade cancers are also unique because they can affect younger men and have a relative resistance to radiation.

• Medical Research News, Published: 2007 Feb 22

A microRNA directly regulates a gene implicated in human cancers, researchers from Whitehead Institute and Massachusetts Institute of Technology report in the February 22nd online issue of Science.

MicroRNAs are tiny snippets of RNA that can repress activity of a gene by targeting the gene's messenger RNA (which copies DNA information and starts the process of protein production).

The first microRNA was discovered in 1993, in worms. It took seven years for the second one to be found, also in worms, but then the floodgates burst. Many microRNAs now have been found in diverse plants and animals, including hundreds in humans. Moreover, microRNAs found in mammals regulate over a third of the human genome, as shown in a 2005 study by the lab of Whitehead Member and Howard Hughes Medical Institute Investigator David Bartel and colleagues.

But given the wealth of