Molecular movements could lead to new way to treat cancer

ScienceDaily (June 6, 2011) — Work by researchers at Queen Mary, University of London could point to a new way to treat aggressive types of cancer. The scientists have found that a molecule called Met is responsible for stimulating the growth and spread of cancer because it is relocating to the wrong part of the cell.

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Experiments in the lab suggest that moving Met molecules from the inside of the cell to the cell surface could halt the growth of cancer cells and even cause tumours to shrink.

Met molecules are involved in the growth of cells in the human body but they are usually only active in a growing embryo or in wound-healing.

However, Met has also been found in many different types of tumour, including breast and lung cancers, where cells are growing uncontrollably. And tumours with high levels of Met tend to be the most aggressive.

Previous research on Met and similar molecules has attempted to tackle the problem by completely blocking the molecule but this has only achieved limited results.

In this new study, published in the journal Nature Cell Biology, the researchers instead attempted to chemically relocate Met to a different part of the cancer cells. Using this approach they were able to halt the growth of cancer cells in the lab and shrink tumours in mice.

The researchers say the study is still in its very early stages but, in the future, it could point the way to a new treatment for cancers.

Dr Stéphanie Kermorgant, who led the study, is a Lecturer in Cellular Oncology at Barts Cancer Institute, part of Queen Mary, University of London. She said: "Previous research has indicated that Met has a role in the development of cancer. We've made a fascinating discovery that, in some cancer cells, this molecule is not only present but it's located in the wrong part of the cell -- it would normally be on the outside of the cell and we've found it on the inside.

"Our study shows that it's not only the presence of the molecule but also where it is in the cell that may promote cancer. We've also shown that we may be able to take advantage of this discovery to design new types of drugs.

"Scientists have been trying to create new cancer drugs by testing chemicals that block Met, or other similar molecules, but results have been mixed.

"Our findings led us to try a new approach -- using a chemical to prevent Met molecules going to the wrong part of the cell. Importantly, this method works even when blocking Met does not work.

"It's early days but this approach looks promising and could eventually lead to new drugs for treating these aggressive types of cancer."

The researchers were funded by the Medical Research Council and Barts and the London Charitable Foundation.

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Tai chi could help overcome cognitive effects of chemotherapy, evidence suggests

ScienceDaily (June 7, 2011) — According to the American Cancer Society, more than 11.4 million Americans are currently living with cancer. While cancer treatments are plentiful, many have negative side effects. Previous studies have indicated that a significant number of patients who receive chemotherapy also experience cognitive declines, including decreases in verbal fluency and memory. Now, one University of Missouri health psychologist has found evidence that indicates Tai Chi, a Chinese martial art, might help overcome some of those problems.

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"Scientists have known for years that Tai Chi positively impacts physical and emotional health, but this small study also uncovered evidence that it might help cognitive functioning as well," said Stephanie Reid-Arndt, assistant professor and chair of the Department of Health Psychology in the School of Health Professions. "We know this activity can help people with their quality of life in general, and with this new study, we are encouraged about how Tai Chi could also help those who have received chemotherapy. I also hope this encourages more people to think about Tai Chi positively on a broader scale in their lives."

Tai Chi involves practicing slow motion routines and is based on several principles, including mindfulness, breathing awareness, active relaxation and slow movements. The emphasis on slow movement makes Tai Chi particularly suited to a wide range of fitness levels, which makes it very relevant for those who have had chemotherapy and might be experiencing physical limitations as a result, Reid-Arndt said.

The MU pilot study followed a group of women with a history of chemotherapy. The women participated in a 60-minute Tai Chi class two times a week for 10 weeks. The women were tested on memory, language, attention, stress, mood and fatigue before and after the 10-week sessions. According to Reid-Arndt, the results of the tests indicated that the women had made significant improvements in their psychological health and cognitive abilities.

"Tai Chi really helps individuals focus their attention, and this study also demonstrates how good Tai Chi could be for anyone, whether or not they have undergone treatment for cancer," Reid-Arndt said. "Due to the small size of this study, we really need to test a larger group of individuals to gain a better understanding of the specific benefits of this activity for patients who have been treated with chemotherapy and how significant these improvements might be."

The study was published recently in Complementary Therapies in Clinical Practice.

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Simple test could hold key to early diagnosis of cancers

ScienceDaily (June 10, 2011) — Cancers of the gut, stomach and pancreas could be detected much sooner with a simple urine test, research suggests. Researchers at the University of Edinburgh have identified key proteins in the urine of patients with advanced cancers.

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The findings could help the detection of these cancers in people who have not yet started to show symptoms of the disease.

This would enable patients to be diagnosed much earlier, leading to improved survival rates.

Only around 10 per cent of patients with these cancers -- known as cancers of the upper gastrointestinal tract -- are still alive five years after diagnosis.

This is because such cancers, which tend to be aggressive, are often diagnosed at an advanced stage.

Dr Holger Husi, of the University of Edinburgh's Tissue Injury and Repair Group, said: "The aim of this work is to enable these cancers to be diagnosed much earlier. This would help us to treat the cancer before it has a chance to spread. The majority of these cancers are currently diagnosed late where no surgery is possible due to its advanced stage. Earlier diagnosis would mean that curative surgery or chemotherapy would be possible for more patients."

The research, published in the journal Proteomics-Clinical Applications, compared urine samples from patients with upper gastrointestinal cancers with urine samples from people who were cancer-free.

Scientists analysed the samples to identify thousands of proteins. They then identified six particular proteins, which were present in 98 per cent of the cancer cases but absent in almost 90 per cent of samples from patients without cancer.

The researchers then narrowed molecules down to the two proteins -- S100A6 and S1009 -- most likely to appear in samples from patients with cancer but be absent from the other samples.

The scientists now intend to see whether people with early stage cancers, which have not yet been diagnosed, have the same levels of proteins present.

This would involve analysing samples from at least 1,000 volunteers and tracking the participants over a number of years to identify those who are then later diagnosed with upper gastrointestinal cancers.

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Cystic fibrosis-associated bacteria could help fight back against antibiotic resistance

ScienceDaily (May 28, 2011) — A bacteria which infects people with cystic fibrosis could help combat other antibiotic-resistant microbes, according to a team from Cardiff and Warwick Universities. Continuous use of existing antibiotics means that resistant bacteria are now causing major health problems all over the world. New antibiotics are urgently needed to combat the emergence of multidrug-resistant bacteria such as the MRSA superbug.

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Now a surprising source of hope has emerged in the form of Burkholderia, a group of bacteria which can cause severe lung infections in people with the genetic disorder cystic fibrosis. However, the Cardiff and Warwick team has now discovered antibiotics from Burkholderia are effective against MRSA and even other cystic fibrosis infecting bacteria.

Dr Eshwar Mahenthiralingam, of Cardiff University's School of Biosciences, Cardiff University, has been studying Burkholderia for the last decade. Using forensic fingerprinting tests to genetically identify the bacteria, Dr Mahenthiralingam's research group has tracked strains all over the world and helped develop guidelines to prevent it spreading.

By the summer of 2007, Dr Mahenthiralingam had built up a large collection of Burkholderia bacteria. He and his team then decided to screen them for antibiotics active against other bacteria, particularly drugs with the potential to kill other bacteria that infect cystic fibrosis patients. Over the next two years, Dr Mahenthiralingam's team discovered that around one quarter of Burkholderia bacteria have very strong antibiotic activity on multidrug-resistant pathogens such as MRSA. One particular strain, Burkholderia ambifaria, was found to produce two very potent antibiotics active on resistant bacteria, in particular Acinetobacter baumanii.

The chemical structures of the antibiotics, called enacyloxins, were determined by Professor Gregory Challis and Dr. Lijiang Song at the University of Warwick, demonstrating that they belong to one of the most successful families of natural product drugs, the polyketides. Other examples of polyketides include erythromycin, which is used to cure many bacterial infections, and doxorubin, used as an anti-cancer drug. Professor Challis commented: "The combination of enzymes used by Burkholderia to make the enacyloxins is very unusual. Our insights into this process should allow us to use cutting edge synthetic biology techniques to produce novel enacyloxin analogues with improved pharmaceutical properties."

The team's findings have now been published in the journal Chemistry and Biology. Dr Mahenthiralingam commented: "Burkholderia are soil bacteria like Streptomyces, which are the source of most of our current antibiotics. Our research therefore offers real hope of a completely new source for the identification and engineering of highly potent antibiotics. With antibiotic resistant bacteria causing great suffering around the world, these new sources are urgently needed."

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Kidney cancer discovery could expand treatment options

ScienceDaily (June 1, 2011) — Oregon Health & Science University Knight Cancer Institute researchers uncovered a gene that may be the key to helping kidney cancer patients who don't respond to current therapies. This discovery could also provide a toolkit to identify patients who are most likely to benefit from drugs that block this gene from causing cancer cells to grow.

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The OHSU study, published in the June 1 edition of Science Translational Medicine, identified a gene called Src that helps certain kidney cancers grow. Discovering that Src plays a role in kidney cancer could help in delivering more effective, individualized treatments to patients, said George Thomas, M.D., the study's senior author and a surgical pathologist at the OHSU Knight Cancer Institute.

The next step, Thomas said, is initiating clinical trials to test how these tumors respond to drugs already available and approved by the FDA.

There are many implications for the Src findings. Last year alone, kidney cancer accounted for about 58,000 new cases of cancer and 13,000 deaths in the United States. More than a quarter of these patients have metastatic disease when their cancer is discovered, and patients who are treated with surgery frequently relapse.

Currently, treatment of kidney cancer is primarily focused on blocking the formation of new blood vessels. While this strategy has been successful in the short term, it does not cure the patient and, more importantly, there are subgroups of patients who don't experience any benefit from these drugs.

"Our preclinical tests found that cancer cells that have increased Src activity were more sensitive to dasatinib (Sprycel), an FDA-approved drug that inhibits Src, both in tissue culture and when grown as tumors in mice," Thomas said.

But there's also a kicker. Thomas and his colleagues developed a panel of clinical markers that could potentially select patients most likely to benefit from Src inhibitors.

Thomas credits the multidisciplinary approach for the study's success. The importance of Src was discovered because of a sophisticated mass spectrometry based assay, called a phospho-proteomics that analyzes activated proteins.

"We had hypothesized that phospho-proteomic screens could rapidly uncover proteins that could be targets for drugs, so that is why we pursued this line of research," Thomas said.

When the screening process suggested that the Src signaling network was activated, indicating that it was playing a role in the growth of cancer cells, it was a surprise. "Src was certainly was not on my radar," Thomas said.

The next step was to look at the role of Src expression in tumor tissues from patients who had previously had their kidney cancers removed.

"We found that patients with tumors expressing high levels of Src had worse survival rates than those patients whose tumors had weak expression of Src. This suggested to us that Src played a role in kidney cancer and that it was a therapeutic target worth exploring."

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New discoveries about tumor-suppressing protein could help reduce treatment side effects

ScienceDaily (May 12, 2011) — Researchers at the Stanford University School of Medicine have untangled two distinct ways in which a common, naturally occurring "tumor-suppressor" protein works. The separation of these two functions -- which can have quite different consequences -- could enhance efforts to develop treatment approaches that mitigate the sometimes-devastating side effects of radiotherapy and chemotherapy.

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The protein, p53, is mutated or missing in more than half of all human cancers, and most cancers involve at least some compromise in its function.

Cancer is caused by two categories of mutations: those that activate oncogenes, whose protein products drive cells into overzealous replication, and those that disable tumor-suppressor genes, which code for proteins that sense this abnormal behavior and put the brakes on it.

"We knew that p53 responds to two different types of signals: DNA damage and oncogene activity," said Laura Attardi, PhD, associate professor of radiation oncology and of genetics. "We wanted to know if p53 responds to both in the same way." Attardi is senior author of a study to be published May 13 in Cell that throws light on crucial molecular details about how p53 works.

It is widely understood that p53 can temporarily or permanently shut down cell division in response to either acute damage to a cell's DNA or biochemical signals within a cell that suggest it's prone to becoming a cancer cell. In extreme cases, p53 convincingly counsels the cell to commit suicide, thereby preventing the possibility of a tumor arising.

Attardi and her colleagues created bioengineered mice in which various parts of p53 were incapacitated. This allowed them to determine which genes are activated by different parts of the protein, and to show that p53's aggressive DNA-damage response and its gentler tumor-suppression response are separable functions.

"We've determined, for the first time, that the gene expression program p53 requires in its tumor-suppression role is distinct from that which it requires in the context of acute DNA damage," Attardi said. "Separating these responses may allow the identification of ways to inhibit the detrimental effects of radiotherapy and chemotherapy -- both of which damage DNA -- without putting a patient at risk for developing new tumors."

While most tumors lack a working p53 protein, radiotherapy and chemotherapy activate the p53 present in healthy tissues, producing serious side effects by destroying cells in the gastrointestinal tract, blood, hair follicles and brain. That's because these treatments cause profound DNA damage, a trigger for p53 action.

It's known that p53 is a transcription factor: a protein that can regulate the production of numerous other proteins inside a cell. According to scientists, p53 recognizes and perches upon a particular DNA sequence found near large numbers of genes. Once p53 has seated itself near such a gene, two different regions of the protein, called TAD1 and TAD2, can serve as landing beacons that attract mammoth molecular copying machines to the gene -- a key early step in protein generation.

But the response is very different depending on which of the two beacons, TAD1 or TAD2, is calling in the copying machinery.

Attardi's group used bioengineered mice in which TAD1, TAD2 or both had been disabled by mutations. This allowed the investigators to show that these two beacons flag different sets of genes.

The genes that TAD1 turns on are the ones involved in p53's show-stopping response to DNA-damage. More than 100 such genes had already been identified.

But when the investigators disabled TAD1 while leaving TAD2 intact, they were able to unmask a set of 50 or so genes turned on by TAD2. These genes, the team showed, mediate p53's ability to stimulate cells' somewhat more nuanced tumor-suppression response, which shuts down a cell only upon sensing oncogene activity, a more direct sign of potential cancer than mere DNA damage.

"When we treated the TAD1-disabled mice with high-dose radiation, they didn't suffer the DNA-damage-induced side effects that we saw in wild-type mice," said the study's lead author, Colleen Brady, a PhD student in Attardi's lab. "But TAD1-disabled mice were resistant to tumor development."

"This is an important advance," said molecular biologist and oncologist Arnold Levine, PhD, a professor at the Institute of Advanced Studies in Princeton, N.J. "The team has uncovered half of what the biggest player in human cancers does." Levine, who didn't participate in the study but is familiar with it, is one of three scientists credited for p53's discovery in 1979.

The finding that p53 can suppress tumors, even when the part of it that shuts down cells in response to DNA damage has been disabled, holds significant implications for therapy. If the two distinct activities of p53 in healthy cells can be decoupled -- say, by a drug impairing TAD1's function but sparing TAD2's -- it might be possible to avoid the massive healthy-cell die-off responsible for nausea, hair loss, immune deficiency and nerve damage that usually occur during radiotherapy or chemotherapy, without promoting new tumor development. Disabling p53's TAD1 region would allow cells that have sustained DNA damage in the course of these therapies to live to another day, but TAD2's still-intact tumor-suppressor function in those otherwise normal cells would guard against those cells becoming cancer cells.

The study was funded by the American Cancer Society, the Leukemia & Lymphoma Society and the National Institutes of Health. Other Stanford co-authors were postdoctoral researchers Dadi Jiang, PhD; Stephano Spano Mello, PhD; Daniela Kenzelmann Broz, PhD; Lesley Jarvis, MD, PhD; and Shashwati Basak, PhD; medical students Margaret Kozak and Thomas Johnson, PhD; and research assistant Eunice Park, all of Attardi's lab. Jarvis is now an assistant professor of medicine at Dartmouth-Hitchcock Medical Center, and Basak is scientific manager at BBRC Syngene International Ltd.

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Half of prostate cancers could potentially benefit from new type of cancer drugs

ScienceDaily (May 19, 2011) — About half of prostate cancers have a genetic anomaly that appears to make tumor cells responsive to a new class of cancer-fighting drugs, a new study from the University of Michigan Comprehensive Cancer Center finds.

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The drugs, called PARP inhibitors, are currently being tested in breast cancer patients with mutations in the BRCA1 and BRCA2 genes, which are found in up to 10 percent of all breast cancers.

Half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, M.D., Ph.D.

"This type of gene fusion occurs in about 50 percent of prostate cancers, but the genes involved have been notoriously difficult to target therapeutically. We found that instead of targeting the gene fusion product directly, we could block the function of critical interacting partners, such as PARP1," says Chinnaiyan, a Howard Hughes Medical Institute researcher, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.

Chinnaiyan is the senior author of the current study, which appears in the May 17 issue of Cancer Cell.

"Our studies suggest that the total population of patients who could benefit from PARP inhibition could be significantly expanded," says Chad Brenner, Ph.D. candidate at U-M, who is the first author on the study.

Working with prostate cancer models in cell lines and mice, researchers found that therapies using the PARP inhibitor Olaparib helped shrink tumors expressing the TMPRSS2:ERG gene fusion and blocked the ability of tumors to spread. Olaparib had no effect on tumors that did not have the gene fusion.

PARP inhibitors are not currently approved by the U.S. Food and Drug Administration, but initial trials in breast cancer patients indicate they can be administered safely and are well-tolerated.

Study authors Maha Hussain, M.D., and Felix Y. Feng, M.D., are currently working on two clinical trials based on these study findings to test if the TMPRSS2:ERG gene fusion could be used as to predict response to treatments, including a PARP inhibitor. These studies are not yet recruiting participants.

Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society

Additional authors: Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel, Xiaoju Wang, Hallie Liang, Jindan Yu, Nallasivam Palanisamy, Javed Siddiqui, Wei Yan, Xuhong Cao, Rohit Mehra, Aaron Sabolch, Venkatesha Basrur, Robert J. Lonigro, Scott A. Tomlins, Christopher A. Maher, Kojo S.J. Elenitoba-Johnson, Kenneth J. Pienta, Sooryanarayana Varambally, all from U-M; Jun Yang, Nora M. Navone, from M.D. Anderson Cancer Center

Funding: National Institutes of Health, U-M Prostate Specialized Program in Research Excellence grant, Early Detection Research Network, U.S. Department of Defense, Prostate Cancer Foundation

The University of Michigan has received a patent on the detection of gene fusions in prostate cancer (US 7,718,369), on which Tomlins and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe.

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