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Agent orange chemical, dioxin, attacks the mitochondria to cause cancer, says Penn research team

Contact: Jordan Reese
jreese@upenn.edu
215-573-6604
University of Pennsylvania

PHILADELPHIA— Researchers with the University of Pennsylvania School of Veterinary Medicine have demonstrated the process by which the cancer-causing chemical dioxin attacks the cellular machinery, disrupts normal cellular function and ultimately promotes tumor progression.

The team identified for the first time that mitochondria, the cellular sub-units that convert oxygen and nutrients into cellular fuel, are the target of tetrachlorodibenzodioxin, or TCDD. The study showed that TCDD induces mitochondria-to-nucleus stress signaling, which in turn induces the expression of cell nucleus genes associated with tumor promotion and metastasis.

The mechanism the research team has described is directly relevant to understanding incidences of breast and other cancers in human populations exposed to these chemicals. With a better understanding of this underlying cellular mechanism, researchers hope to improve their understanding of tumor growth and promotion.

“Now that we have identified this signaling mechanism we can look at ways to disrupt this complex chain of events,” said Narayah Avadhani, chair of the Department of Animal Biology at Penn’s School of Veterinary Medicine and the study’s lead investigator. “Our ultimate goal is to block the propagation of this mitochondrial stress signaling and inhibit the expression of the proteins that combine to assist cancer growth.”

A well-characterized mechanism of TCDD action occurs through activation of arylhydrocarbon receptors, AhR, by directly binding to the protein subunits. Activated AhR mediates the transcriptional activation of many genes including those involved in fatty acid metabolism, cell cycle regulation and immune response. The present study, however, shows that TCDD starts the chain of events that promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling. A unique feature of this TCDD-induced signaling is that it does not involve the action of AhR but occurs through increased calcium levels in cells and activation of calcium responsive factors. A net result of signaling cascade is slowing down of cellular apoptosis, increased cell proliferation and tumor cell metastasis. Taken together, this study describes a novel mechanism of TCDD-induced tumor progression and emergence of metastatic cancer cells.

TCDD is the most toxic compound in the dioxin family. Formed as a by-product during waste incineration, paper, chemical and pesticide manufacturing, it was the toxic ingredient in Agent Orange and closed the Love Canal in Niagara Falls. The public health impact of dioxin, according to the Environmental Protection Agency, compares to that of the pesticide DDT.

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The study appears online and in the Dec. 17 issue of the Proceedings of the National Academy of Sciences and was performed by Avadhani, Gopa Biswas, Satish Srinivasan and Hindupur Anandatheerthavarada of the Penn School of Veterinary Medicine.

The research was supported by a grant from the National Cancer Institute and the National Institutes of Health.

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December 18, 2007 Posted by | Cancer, Cancer Biology, FMS Global News, Global, Global News, London, London UK Feed, National Cancer Institute, NIH, Ottawa, Ottawa City Feed, PTSD, RSS Feed, Toronto, Toronto City Feed, Washington DC, Washington DC City Feed, World News | , , , , | Leave a comment

Demand for Spanish-language cancer Web materials quadruples

Contact: Beth Bukata
bethb@astro.org
703-431-2332
American Society for Therapeutic Radiology and Oncology

Internet resources and access remain scarce

Although Spanish-speaking cancer patients are rapidly increasing their search for patient education resources on the Internet, there are very few Spanish-language Web sites available to provide this information, according to a study presented October 28, 2007, at the American Society for Therapeutic Radiology and Oncology’s 49th Annual Meeting in Los Angeles.

Spanish-speaking cancer patients were also shown to have more limited access to the Internet compared to English-speaking users of cancer information Web sites, based on the user patterns of the two groups.

“There is an urgent need for more Web-based information to be more available to Spanish-speaking patients with cancer, and Internet access needs to be more widely available,” said Charles Simone II, M.D., lead author of the study and a radiation oncologist at the Hospital of the University of Pennsylvania in Philadelphia. “The increased knowledge gained among these patients will help to eliminate healthcare disparities and lead to improved medical outcomes.”

The Spanish-language cancer information Web site, OncoLink en español, quadrupled their number of unique visitors last year, from 7,000 visitors per month in January 2006 to nearly 29,000 monthly visitors by the end of the year. More than 200,000 users visited the Web site in 2006.

In contrast, the English-language version of the site, OncoLink, had nearly 2 million visitors last year, although their number of unique visitors did not increase throughout the year. OncoLink en espanõl was launched in 2005 by OncoLink, one of the oldest and largest Internet-based cancer information resources. Both sites are managed by the University of Pennsylvania.

The study shows that OncoLink en español users were less likely to browse the Internet during weekends and morning hours, compared to the users who browsed OncoLink, suggesting that they are accessing the Internet more through work or specialized services.

In addition to when they accessed the Internet, OncoLink en español users also differed on the types of cancers they searched for, as well as the timing and method of their Internet search patterns.

“Awareness of these differences can assist cancer education Web sites to tailor their content to best meet the needs of their Spanish-speaking users,” said Dr. Simone.

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The study was carried out using AWStats, a Web-data analyzing program, to collect and compare statistical data from the secure servers of both language versions of OncoLink.

For more information on radiation therapy in English and in Spanish, visit http://www.rtanswers.org.

The abstract, “The Utilization of Radiation Oncology Web-based Resources in Spanish-speaking Oncology Patients,” will be presented for poster viewing starting at 10:00 a.m, Sunday, October 28, 2007. To speak to the study author, Charles Simone, II, M.D, please call Beth Bukata or Nicole Napoli October 28-31, 2007, in the ASTRO Press Room at the Los Angeles Convention Center at 213-743-6222 or 213-743-6223. You may also e-mail them at bethb@astro.org or nicolen@astro.org.

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October 29, 2007 Posted by | Cancer, Cancer Information In Spanish, FMS Global News, Global, Global Health Vision, Global News, London, London UK Feed, Lung Cancer, News, Oncology, Ottawa, Ottawa City Feed, Research, RSS Feed, Spanish, Toronto, Toronto City Feed, Washington DC City Feed | , , , | 7 Comments

Political decisions harming cancer treatment in Europe

Time to stand up and be counted, say oncologists

Barcelona, Spain: Recent political decisions have had serious consequences for European oncology, said Professor John Smyth at ECCO 14, the European Cancer Conference, today (Monday 24 September 2007). Professor Smyth, President of the Federation of European Cancer Societies (FECS) said that the new European CanCer Organisation (ECCO) would take an active role in engaging with policymakers to ensure that future legislation did not have a similarly negative impact.

Professor Smyth cited the Clinical Trials Directive and the recent Directive on Physical Agents (Electromagnetic Fields) as two examples of legislation that had had a major negative impact on oncology in Europe. “In the first, the academic oncology community woke up too late and found that the administrative and financial burden of running clinical trials had increased to the extent that many simply gave up,” he said. “Now the Directive on Electromagnetic Fields looks as though it may stop all MRI scanning in Europe. We simply cannot continue to bury our heads in the sand on these issues, which affect doctors and patients alike.”

Forthcoming topics of concern were the problems of international collaboration on stem cell research where European countries had widely differing legislation, and the whole area of the escalating cost of cancer treatment. “The successful development of many new anti-cancer drugs in recent years is challenging every health economic programme in Europe,” said Professor Smyth. “It is imperative to find ways to improve the cost effectiveness of cancer treatment in general, and particularly the use of drugs. Improving the cost effective use of medicines is a major priority for industry, politicians and the public at large.

“Due to these new and improved treatments, screening, and earlier and better diagnosis, cancer patients are living longer and better lives. But how will the huge financial burden on society that this implies be met” ECCO will be asking governments and the European Commission to consider these issues as a matter or urgency.”

ECCO will bring together major players in cancer research, treatment, and care in order to create awareness of patients’ wishes and needs, encourage progressive thinking in cancer policy, education, and training, and continue to promote European cancer research and its application through the organisation of multi-disciplinary meetings and conferences, he said.

“The difference between the new ECCO and the old FECS will be that the new organisation has decided to take a far more active role in engaging with policymakers to promote the interests of both cancer patients, those who care for them; and those without whose research there would be no advances in treatment and care,” he said. “For too long oncologists have sat back and said that getting involved in politics is not their business, and recent events have shown us that this is an attitude which is no longer sustainable.”

The last two years had given ample opportunity for reflection, said Professor Smyth. “Not only did we consult our members, but we also carried out an audit of many players in oncology, patient groups, media, and other stakeholders. They all told us the same thing – they wanted to see a democratic, representative, and visionary organisation tackle the problems that are currently besetting oncology science and practice. An organisation that would provide consistently dependable information on the state of oncology in Europe, and through that information provision would strive to improve the lot of everyone involved in cancer.

“It is a daunting task, but one that needs to be undertaken. And we will do our very best to carry it out.”

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Notes for Editors:

1. Invitations to join ECCO (http://www.ecco-org.eu/) have been sent to the FECS Founding Members: EACR, EONS, ESSO, ESMO, ESTRO, and SIOP Europe.
Members and Advisory Council: EANO, EORTC, ESGO, ESO, ESOP, Euroskin, and EUSOMA, EBMT, ECL, Europa Donna, FAC, OECI, and UICC.

2. The Clinical Trials Directive 2001/20/EC came into force in 2004. Its aim was to harmonise national legislation on the conduct of clinical trials and to create a level playing field for European clinical research. In fact it seems to have had the opposite effect, with academic researchers finding that the extra administrative and financial burden that it imposes impedes severely their chances of carrying independent, objective research.

3. The Physical Agents (Electromagnetic Fields) Directive 2004/40/EC is intended to protect workers from electromagnetic radiation. However, its implementation in its current form would effectively ban all MRI scanning in Europe, since the limits it sets to occupational radiation exposure would mean that anyone working or moving near MRI equipment will breach them, thus making it possible for them to sue their employers.

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September 24, 2007 Posted by | Cancer, European Cancer Conference, Global Health Vision, Global News, News, News UK | 2 Comments

Cancer patients, spouses report similar emotional distress, U-M study finds

Phase of illness plays large role in distress; Interventions should be targeted to spouses along with patients

ANN ARBOR, Mich. – A cancer diagnosis affects more than just the patient. A new study from researchers at the University of Michigan Comprehensive Cancer Center finds spouses report similar physical and emotional quality of life as the patient.

The study found that what really impacted emotional distress – among both patients and their spouses – was whether the patient was newly diagnosed, facing a recurrence or living with advanced disease.

Researchers looked at 263 men with prostate cancer and their spouses. Participants were recruited from three large cancer centers. Both the men and their wives completed questionnaires that assessed quality of life, including physical, social, family, emotional and functional issues. Patients and spouses each reported on their own quality of life.

The researchers found little difference in quality of life between patients and spouses, but found significant differences based on the phase of their illness. Couples coping with advanced disease had significantly poorer overall quality of life.

“The spouses of advanced cancer patients are really carrying the load. Cancer is a devastating illness, and a patient’s primary resource is the partner, who often doesn’t have the information she needs to deal with these complex problems. This isn’t just a common cold – this is the person you love and care about dealing with a life-threatening illness,” says lead study author Laurel Northouse, Ph.D., R.N., co-director of the Socio-Behavioral Program at the U-M Comprehensive Cancer Center and Mary Lou Willard French Professor of Nursing at the U-M School of Nursing.

Results of the study appear in the Sept. 20 issue of the Journal of Clinical Oncology.

Spouses reported lower confidence than patients in their ability to manage the illness, and more uncertainty about the illness. Patients also reported more social support than did spouses.

“Doctors, nurses and even family and friends often focus mainly on the patient who has cancer and don’t realize the illness has enormous ramifications on the family, especially the spouse,” Northouse says.

The researchers urge more health care interventions aimed at emotional distress for both patients and caregivers. At the same time, caregivers should recognize they too are emotionally affected by this illness and seek appropriate support. Patients also can play a role by encouraging their spouse to be actively involved in their care.

“Patients need to recognize this illness affects their partners as well as themselves. They need to find a way to be supportive of their partner; for example, including them in interactions with physicians so the partners get the information they desperately want. Work as a team together to deal with the illness. I think patients may underestimate the needs of their partners to get information. Those partners need first-hand information. If they’re able to go into the consultation, they’re able to get their questions answered,” Northouse says.

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In addition to Northouse, study authors were James Montie, M.D., Valassis Professor of Urologic Oncology and chair of urology at U-M; Howard Sandler, M.D., U-M professor of radiation oncology; Maha Hussain, M.D., U-M professor of internal medicine and urology; Kenneth Pienta, M.D., U-M professor of internal medicine and urology; David Smith, M.D., U-M professor of internal medicine and urology; Darlene Mood, Ph.D., and Jeffrey Forman, M.D., both from Wayne State University and Karmanos Cancer Center; Martin Sanda, M.D., from Harvard Medical School; and Trace Kershaw, Ph.D., from Yale University.

Funding for the study was from the National Cancer Institute.

Reference: Journal of Clinical Oncology, Vol. 25, No. 27, Sept. 20, 2007

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

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September 20, 2007 Posted by | Cancer, Global Health Vision, Global News, University of Michigan, Washington DC City Feed | 1 Comment

Intercampus initiative works to increase participation in clinical trials; first phase of study to focus on cancer

Sept. 13, 2007

NEW YORK — Before a new treatment becomes available, researchers must recruit hundreds or thousands of patients to participate in clinical research trials. But finding these patients is often difficult. Many potential candidates are unaware of the studies or unable to participate due do logistical hurdles. As a result, patients miss out on opportunities for novel treatment approaches — and beneficial new therapies take longer to reach the public.

In a new initiative, researchers at Weill Cornell Medical College (WCMC) and Cornell’s College of Agriculture and Life Sciences (CALS) have teamed up to develop strategies to better understand and enhance patient participation in clinical trials. The project, called Improving Methods for Patient Accrual to Clinical Trials (IMPACT), is one of several recent efforts at WCMC to foster clinical research programs across the medical spectrum.

“Low patient accrual in clinical trials poses a serious problem for the advancement of medical science,” said John Leonard, professor of medicine at WCMC, attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and co-leader of the study.

The time required to conduct clinical trials is widely recognized as a limiting step in moving novel treatments forward, Leonard said. For example, less than 2 percent of patients choose to participate in clinical trials for cancer therapies across the United States. Even a modest increase of 2 to 3 percentage points would make a major impact, meaning the difference between completing a study in two years instead of three years — and potentially resulting in thousands of lives saved if the standard of care is improved more rapidly.

“Hundreds of studies have sought to identify and overcome barriers to enrollment. This project is the first to assess the problem from a socio-psychological perspective using the specialized methods of risk communication,” said Katherine McComas, principal leader of IMPACT and assistant professor of communication at Cornell. “We will be using two proven approaches — the model of Risk Information Seeking and Processing, and Theory of Planned Behavior. These will allow us to examine specific factors that influence how patients inform themselves about a clinical trial and decide whether to participate.”

IMPACT investigators will collaborate with The Leukemia and Lymphoma Society, which has helped finance the first phase of the project, including a national survey on attitudes toward participation in clinical trials. The funding will also support a doctoral student in the Department of Communication.

“Our aim is to provide data-supported recommendations for strategies to improve the accrual of patients in clinical trials,” said Andrew Dannenberg, also a co-leader of the IMPACT project, professor of medicine at WCMC and attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Future phases of the study will develop specific tools to better educate patients about clinical trials and break down common barriers to participation, Dannenberg added, “so that new therapies for many disorders can be more rapidly designed and evaluated in order to deliver their maximal benefit.”

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September 17, 2007 Posted by | Cancer, Clinical Trials, Cornell University, Global Health Vision, Global News, News | 2 Comments

Bits of ‘junk’ RNA aid master tumor-suppressor gene

Loss is linked to common lung cancer

Little-known bits of RNA help master tumor-suppressor gene do its job, U-M cancer researchers find

Three micro RNA genes appear to be key partners of protective gene p53; their loss is linked to common type of lung cancer

ANN ARBOR, Mich. — Scientists have shown in literally thousands of studies that the p53 gene deserves its reputation as “the guardian of the genome.” It calls to action an army of other genes in the setting of varied cell stresses, permitting repair of damaged DNA or promoting cell death when the cell damage is too great. A key net effect of p53’s action is to prevent development of cancerous cells.

Now, University of Michigan Medical School scientists provide the most thorough evidence yet that p53 also regulates a trio of genes from the realm of so-called “junk” genes — the roughly 97 percent of a cell’s genetic material whose function is only beginning to be understood.

The study shows that “in the ‘junk’ lies treasure, in terms of critical knowledge about how normal cells stifle cancer or succumb to it,” says Guido Bommer, M.D., the lead author of results, published in a recent issue of the journal Current Biology.

“The findings in the study offer new insights into specific mechanisms by which the expression of hundreds to thousands of genes and proteins is altered in the roughly 50 percent of cancers that carry mutations in the p53 tumor suppressor gene,” says Eric Fearon, M.D., Ph.D., senior author of the study and deputy director of the U-M Comprehensive Cancer Center. Scientists continue to mine for details of what goes wrong when p53 is defective and cannot perform its tumor-fighting duties.

The U-M study is one of four recent studies from labs around the world showing that p53 normally gets support from members of a small family of micro RNA genes. The studies are part of a larger effort to understand the function of micro RNA (miRNA for short).

Scientists have long known the importance of messenger RNA (mRNA), which carries protein-making instructions. However, until recently, little was known about micro RNA genes. It is now well recognized that miRNAs regulate the levels of mRNAs, and/or the levels of the proteins produced from mRNAs.

The U-M research team studied the roles of the three genes that make up the miRNA34 family. They showed that the miRNA34 genes work in concert with p53, then went on to explore which other genes the family regulates. They found the miRNA34 genes showed pronounced effects on other genes that control the timing of cell proliferation and division. They also found that the miRNA34 gene family regulated the levels of the Bcl-2 protein, a key factor that enhances a cell’s resistance to death-inducing stimuli.

The team went on to determine if expression of the miRNA34 genes was compromised in human lung cancer cells.

“We found that expression of two of the miRNA34 genes was lost in almost two-thirds of lung adenocarcinomas,” says Bommer.

Adenocarcinomas represent the most common type of non-small cell lung cancer, which is the most frequently diagnosed type of lung cancer. When expression of the miRNA34 genes was restored in lung cancer cells, some of the aberrant growth properties were inhibited.

The discoveries of the role of micro RNAs in tumor suppression could have implications for future cancer therapies.

It’s important to note that micro RNAs alone are not likely to offer new cancer treatment or prevention agents, says Fearon, who is the Emanual N Maisel Professor of Oncology, Professor of Internal Medicine, Professor of Pathology and Professor of Human Genetics at the U-M Medical School.

“However, because of the small size of mature miRNAs, there is optimism that it may be possible to deliver modified nucleic acids that might mimic the effect of the miRNAs,” he says. If modified nucleic acids were to prove effective in more laboratory studies, he adds, they might be pursued further in clinical trials as anti-cancer agents, either alone or more likely in combination with other anti-cancer agents.

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In addition to Bommer and Fearon, other U-M authors include: Isabelle Gerin, Ph.D.; Ying Feng, Ph.D.; Andrew J Kaczorowski, B.S.; Rork Kuick, Ph.D.; Robert E Love , B.S.; Yali Zhai, M.D., Ph.D.; Thomas J Giordano, M.D., Ph.D.; Zhaohui S Qin, Ph.D.; Bethany B Moore, Ph.D.; Ormond A MacDougald, Ph.D.; and Kathleen R Cho, M..D., Ph.D.

This research was funded by the National Institutes of Health.

Citation: Current Biology 17, 1298–1307, August 7, 2007

Contact: Anne Rueter
arueter@umich.edu
734-764-2220
University of Michigan Health System

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August 23, 2007 Posted by | Cancer, Genetic, Genetics, Global Health Vision, Global News | 3 Comments

Can cancer drugs combine forces?

Individuals with chronic myeloid leukemia (CML) are treated first with a drug known as imatinib (Gleevec), which targets the protein known to cause the cancer (BCR-ABL). If their disease returns, because BCR-ABL mutants emerge that are resistant to the effects of imatinib, individuals are treated with a drug known as dasatinib (SPRYCEL), which targets BCR-ABL in a different way. However, patients that relapse after treatment with dasatinib, because BCR-ABL mutants emerge that are resistant to the effects of this drug, are now beginning to be seen in the clinic. Researchers from Memorial Sloan-Kettering Cancer Center, New York, now suggest that treating patients with a combination of the drugs might decrease the chance of the cancer returning, or at the very least increase the time before a relapse occurs

In the study, which appears online on August 16 in advance of publication in the September print issue of the Journal of Clinical Investigation, Charles Sawyers and colleagues show that 2 of 12 patients whose cancer had returned after treatment with dasatinib responded to retreatment with imatinib. Analysis of the BCR-ABL proteins from these patients revealed that their BCR-ABL had only the dasatinib-resistance mutation. By contrast, the BCR-ABL proteins of the other patients had either a single mutation that rendered the protein resistant to both dasatinib and imatinib or had two mutations, one rendering the protein resistant to imatinib and one rendering the protein resistant to dasatinib. A third drug that can target dasatinib- and imatinib-resitant BCR-ABL is currently in clinical trials. The authors therefore suggest that rather than treating CML patients with the drugs that target BCR-ABL sequentially, they should receive all the drugs when they are first diagnosed with the disease so that the emergence of the drug-resistant forms of BCR-ABL might be prevented, or at least delayed.

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TITLE: Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency

AUTHOR CONTACT: Charles L. Sawyers Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Phone: (646) 888-2138; Fax: (646) 888-2595; E-mail: sawyersc@mskcc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30890

Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation

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August 16, 2007 Posted by | Cancer, Global Health Vision, Global News, Health, Leukemia, News UK, News USA | 1 Comment

ESF EURYI award winner aims to stop cancer cells reading their own DNA

A promising new line in anti-cancer therapy by blocking the molecular motors involved in copying genetic information during cell division is being pursued by young Dutch researcher Dr. Nynke Dekker in one of this year’s EURYI award winning projects sponsored by the European Science Foundation (ESF) and the European Heads of Research Councils (EuroHORCS). Dekker and her team are trying to stop tumor development by interfering with the molecular motors that copy DNA during cell division. This will cut off the genetic information flow that tumours need to grow, and could complement existing cancer therapies, while in the longer term bringing the promise of improved outcomes with greatly reduced side effects.

There are three primary ways of treating cancer at present, and these have fundamentally changed little in 30 years. In the case of solid tumours, surgery can be used to cut out the cancerous tissue, while radiation therapy can kill the malignant cells, and chemotherapy stops them dividing. Dekker’s work is aiming towards a new generation of drugs that target cancer cells much more specifically than traditional chemotherapy, avoiding side effects such as temporary hair loss.

Dekker is focusing on an enzyme called Topoisomerase IB that plays a key role in some of the molecular motors involved in the processes of DNA and RNA copying during cell division. These are responsible for reading the genetic code and making sure it is encoded correctly in the daughter cell. In healthy cells it is important that this process works normally, but in cancer cells it is a natural target for disruptive therapy. “Specifically targeting these molecular motors in cancer cells would then prevent the cancer cells from growing into a larger tumor,” said Dekker. This molecular copying machinery, constructed mostly out of proteins, in effect walks along the DNA double helix reading the genetic code so that it can be copied accurately into new DNA during division. Other components of the machinery are responsible for slicing and assembling the DNA itself. All of these are potential targets for anti-cancer therapy, providing it is possible to single out the tumor cells. Most existing chemotherapy targets all dividing cells, and the aim to find more sensitive techniques.

However Dekker’s work is not just confined to cancer, having the broader goal within the ESF EURYI project of unraveling the underlying physical principles behind these molecular motors that operate at the nanometer scale to process and manipulate the information stored within the DNA and RNA of our cells. Dekker is exploiting a variety of new highly sensitive manipulation and imaging techniques capable of resolving single molecules. These include force spectroscopy, new forms of optical microscopy with greatly improved resolving power and field depth, as well as nanotechnologies. The research involves cross-disciplinary work among scientists in different fields with the long term goal of developing more precisely targeted molecular medicines for a variety of diseases involving disruption to normal cellular functions and not just cancer.

Dekker’s work has already shown great promise, and she has been able to predict what effect certain antitumor drugs would have on the basis of her molecular insights, confirming her hypotheses in yeast cells. “Indeed the work with antitumor drugs is, as far as I know, the first experiment in which single-molecule experiments have resulted in a prediction for a cellular effect,” said Dekker.

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Dekker, a 36-year-old Dutch associate professor at the Technische Universiteit Delft in the Netherlands, is currently undertaking single-molecule studies of DNA and RNA and their interactions with proteins, integrated with nanotechnology where appropriate. She gained her PhD in physics at Harvard University, having graduated from Yale.

As well as being awarded multiple grants and fellowship programmes, Dr. Dekker is a member of the Council of the Biophysical Society, and of the Young Academy of the Royal Academy of Arts and Sciences. She is actively involved in conference organization at the interface of biology and physics. Her group’s research has appeared in Nature and in The Proceedings of the National Academy, USA, among others.

The EURYI awards scheme, entering its fourth and final year, is designed to attract outstanding young scientists from around the world to create their own research teams at European research centres and launch potential world-leading research careers. Most awards are between €1,000,000 and €1,250,000, comparable in size to the Nobel Prize. Dekker will receive his award in Helsinki, Finland on 27 September 2007 with other 19 young researchers.

More on Dekker’s work http://www.esf.org/activities/euryi/awards/2007/nynke-hester-dekker.html

More on EURYI: http://www.esf.org/ext-ceo-news-singleview/article/2007-euryi-20-young-researchers-to-receive-nobel-prize-sized-awards-for-breakthrough-ideas-294.html

Contact: Thomas Lau
tlau@esf.org
33-388-762-158
European Science Foundation

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August 9, 2007 Posted by | Cancer, Cancer Biology, European Science Foundation, Genes, Genetic, Genetics, Global, Global Health Vision, Global News, Health, Music Video Of The Day | Leave a comment

Multicenter study nets new lung tumor-suppressor gene

BOSTON–Collaborating scientists in Boston and North Carolina have found that a particular gene can block key steps of the lung cancer process in mice. The researchers report in the journal Nature that LKB1 is not only a “tumor-suppressor” gene for non-small cell lung cancer in mice, it also may be more powerful than other, better-known suppressors. The study will be published on the journal’s Web site on Aug. 5 and later in a print version.

If further research shows LKB1 has a similar effect in human lung cells, it could influence the way non-small cell lung cancer is diagnosed and treated, says the study’s senior author, Kwok-Kin Wong, MD, PhD, of Dana-Farber, one of three institutions, along with Massachusetts General Hospital and the University of North Carolina School of Medicine, leading the work. If tumors with LKB1 mutations are found to be especially fast-growing, for example, patients with such tumors might be candidates for more aggressive therapy.

People born with defective versions of LKB1 often develop Peutz-Jeghers syndrome, which is marked by intestinal growths and an increased risk for certain cancers. Non-inherited mutations of the gene have been found in some lung cancers. This suggested that LKB1 normally thwarts tumors from forming. Mutated versions may be unable to act as a brake on cancer.

To find out, the investigators ran a series of experiments in mice with a defective form of a gene called Kras, which drives the formation and growth of lung cancer. They tracked the development of lung cancer in animals with mutated LKB1 and compared it to the experience of animals with abnormalities in either of two well-known tumor-suppressor genes.

They found that while Kras “cooperated” with the mutated tumor-suppressor genes to produce lung cancer, it cooperated even more strongly with mutated LKB1. “The LKB1-deficient tumors grew more rapidly and spread more frequently than the others, and comprised all three types of non-small cell lung cancer — squamous cell carcinoma, large-cell carcinoma, and adenocarcinoma — rather than just one or two,” Wong says. “This suggests that LKB1 plays a role at major stages of the tumors’ development: initiation, differentiation of normal lung cells into cancer cells, and metastasis.”

An examination of human non-small-cell lung tissue suggests LKB1 mutations play a role there as well. Of 144 samples analyzed, 34 percent of the lung adenocarcinomas and 19 percent of the squamous cell carcinomas contained abnormal versions of the gene, researchers report.

“We were surprised at how significant a role LKB1 mutations play in non-small cell lung cancer development in mice,” say Wong, who is also an assistant professor of medicine at Harvard Medical School. “This suggests there may be additional lung tumor-suppressor genes yet to be discovered. We’re currently examining whether these results apply to human lung cancers as well and, if so, how such information can improve treatment.”

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The lead author of the study was Hongbin Ji, PhD, of Dana-Farber. Other Dana-Farber co-authors include Dongpo Cai, PhD, Liang Chen, PhD, Pasi Janne, MD, PhD, Bruce Johnson, MD, Jussi Koivunen, MD, PhD, Danan Li, Mei-Chih Liang, PhD, Kate McNamara, Matthew Meyerson, MD, PhD, Samanthi Perera, PhD, Geoffrey Shapiro, MD, PhD, and Takeshi Shimamura, PhD. Other authors were based at Children’s Hospital Boston, Brigham and Women’s Hospital, Broad Institute of Harvard University and Massachusetts Institute of Technology, University of Tennessee Health Science Center, and the University of Texas Southwestern Medical Center.

The research was supported by the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the American Federation of Aging, the Joan Scarangello Foundation to Conquer Lung Cancer, the Flight Attendant Medical Research Institute, the Waxman Foundation, the Harvard Stem Cell Institute, and the Linda Verville Foundation.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute

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U-M researchers find family of ‘on switches’ that cause prostate cancer

Gene fusions trigger cancer growth, could impact treatment choices

ANN ARBOR, Mich. — Researchers at the University of Michigan Comprehensive Cancer Center have discovered how genes turn on the switch that leads to prostate cancer.

The team discovered that pieces of two chromosomes can trade places with each other and cause two genes to fuse together. The fused genes then override the “off” switch that keeps cells from growing uncontrollably, causing prostate cancer to develop.

By testing these gene fusions in mice and in cell cultures, the researchers showed that the fusions are what cause prostate cancer to develop. But it’s not just one set of genes that fuse. The researchers found that any one of several in a family of genes can become scrambled and fuse. Results of the study appear in the Aug. 2 issue of Nature.

“Each of these switches, or gene fusions, represent different molecular subtypes. This tells us there’s not just one type of prostate cancer. It’s a more complex disease and potentially needs to be treated differently in each patient,” says lead study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, a new U-M center whose goal is to translate research into real world practice.

The gene fusion research is the centerpiece project of the new center. In the current study, researchers found one of several abnormal gene fusions in the prostate cancer tissue samples they tested. In 2005, the researchers identified a prostate-specific gene called TMPRSS2, which fuses with either ERG or ETV1, two genes known to be involved in several types of cancer.

The Nature paper reports on five additional genes that fuse with ERG or ETV1 to cause prostate cancer. Gene fusions were involved in 60 percent to 70 percent of the prostate cancer cell lines the researchers looked at. The genes involved are all controlled by a different mechanism. For example, four of the genes are regulated by androgen, a male sex hormone known to fuel prostate cancer. Androgen deprivation is a common therapy for prostate cancer.

Knowing which gene fusion is involved in an individual patient’s tumor could impact treatment options. If an androgen-regulated gene is involved, androgen therapy would be appropriate. But if the gene fusion involves a gene that represses androgen, the anti-androgen therapy could encourage the cancer’s growth. This may also explain why androgen treatment is not effective for some prostate cancers.

“Typing someone’s prostate cancer by gene fusion can affect the treatment given. We would not want to give androgen to someone whose prostate cancer gene fusion is not regulated by androgen,” says Chinnaiyan, who is the S.P. Hicks Collegiate Professor of Pathology at the U-M Medical School.

Rearrangements in chromosomes and fused genes are known to play a role in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma. A fused gene combination that plays a role in chronic myelogenous leukemia led researchers to develop the drug Gleevec, which has dramatically improved survival rates for that disease.

Chinnaiyan believes the prostate gene fusions will eventually lead to similar treatments for prostate cancer.

“More immediately, we hope to develop tests for diagnosis or prognosis. But long-term, we hope this will lead to better therapies to treat prostate cancer. The key challenge is to find a drug that would go after this gene fusion,” Chinnaiyan says.

The gene fusion technology has been licensed to San Diego-based Gen-Probe Inc., which is working on a screening tool to detect gene fusions in urine. The tool could one day supplement or replace the prostate specific antigen, or PSA, test currently used to screen for prostate cancer.

The idea of translating laboratory research findings into a test or treatment that will impact patients is central to the new Michigan Center for Translational Pathology. The center brings together experts in genomics, proteomics and bioinformatics to look at common patterns and potential targets in cancer and other diseases. This is the first center of its kind in the nation in that it is associated with one of 39 National Cancer Institute-designated “comprehensive” cancer centers, a premier medical school and a large health system with both clinicians and patients.

The center’s goal is to study the genes, proteins and other markers on cells to develop new diagnostic tests or screening tools as well as targeted treatments for cancer and other diseases, with the key being to translate these laboratory discoveries into clinical applications.

Chinnaiyan and his team have received numerous awards and honors, including the American Association for Cancer Research Team Science Award for their previously published work on gene fusions, and the Specialized Program of Research Excellence Outstanding Investigator award. The new Center for Translational Pathology supported in part by the Prostate Cancer Foundation, which has offered to match up to $1 million dollars in donations to support work related to developing therapies against prostate cancer gene fusions at the university.

“Mapping of the human genome was only the beginning. Equipped with the comprehensive analysis of the human genome, we can now systematically examine the blueprint of disease at the molecular level. This essential knowledge may lead to better diagnostic tests and promising new treatments for cancer, cardiovascular disease, diabetes and other illnesses,” Chinnaiyan says.

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For information about the Michigan Center for Translational Pathology, go to http://www.med.umich.edu/mctp.

About 218,890 men will be diagnosed with prostate cancer this year, and 27,050 will die from the disease, according to the American Cancer Society. The gene fusion work is not currently available for treatment or diagnosis, and no clinical trials are currently recruiting. For information about prostate cancer and currently available treatments, go to http://www.mcancer.org or call the U-M Cancer AnswerLine at 800-865-1125.

In addition to Chinnaiyan, U-M study authors were Scott Tomlins; Saravana Dhanasekaran, Ph.D.; Bharathi Laxman; Qi Cao; Beth Helgeson; Xuhong Cao; David Morris, M.D.; Anjana Menon; Xiaojun Jing; Bo Han; James Montie, M.D.; Kenneth Pienta, M.D.; Diane Roulston; Rajal Shah, M.D.; Sooryanarayana Varambally, Ph.D.; and Rohit Mehra, M.D. Mark Rubin, M.D., from Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School is also a study author.

Funding for the study came from the U.S. Department of Defense, the National Institutes of Health, the Early Detection Research Network, the Prostate Cancer Foundation and Gen-Probe Inc.

The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which Tomlins, Mehra, Rubin 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; however, GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

Reference: Nature, Vol. 448, No. 7153, Aug. 2, 2007

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

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