Personalized Medicine: Tumor Analysis Reveals New Opportunities for Existing Cancer Drugs

Targeted cancer therapies such as trastuzumab (Herceptin), gefitinib (Iressa) and erlotinib (Tarceva) could be used to treat a wider range of cancers than previously thought, according to new research presented November 16 at the 22nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin.

Scientists in the USA have studied 20 genes that are targeted by existing therapies and found that there are significant changes to these genes in a broad range of patients' tumours, including many for which these drugs are not being used at present. The results suggest that these therapies, which have already been deemed safe and effective by regulatory agencies, may have additional opportunities to benefit cancer patients.

However, Dr Daniel Rhodes, chief executive officer and co-founder of Scientific Applications at Compendia Bioscience (Ann Arbor, Michigan, USA), told the meeting: "While there may be immediate opportunities to use these new findings to treat patients with few remaining treatment options, broader application of the findings will require large-scale clinical trials to investigate if such personalised medicine could translate into real benefit over existing standard of care."

Genes can play a role in causing cancer in a number of ways, including via mutations that cause them to function incorrectly or via DNA amplifications whereby there are multiple additional copies of a gene. Normal cells (apart from germ cells) typically have two copies of each gene, but cancer cells often create additional copies of specific cancer-causing genes. For the current study, Dr Rhodes and his colleagues were looking for tumours in which there were five or more copies of a particular gene.

Targeted therapies are aimed at blocking the action of the mutated or amplified genes, "but they are often used without detailed knowledge of the genetic makeup of a patient's tumour," said Dr Rhodes. "The aim of personalised medicine is to understand an individual patient's cancer and select therapies that are most likely to benefit the patient; however, today most patients do not undergo any genetic testing of their tumours. We sought to understand the opportunity to use DNA amplifications, one type of cancer-causing mutation, to select existing targeted therapies that would be most likely to benefit cancer patients.

"We studied 22 genes that are targeted by therapies, either approved or in clinical trials, and found that the targets often show high-level amplifications in small subsets of patients and that particular cancer types show more frequent amplifications, for instance cancers of the brain (21.4% of cases) and breast (23.2% of cases). Our work suggests that some cancer patients should be tested for DNA amplifications and that small subsets of cancer patients harbour specific DNA amplifications that might indicate potential benefit from an existing therapy. We caution that we have not demonstrated that the targeted therapies will benefit all cancer patients with a DNA amplification, but we suspect, given past clinical trials and experimental studies, that some DNA amplifications will be predictive of therapeutic benefit for some patients."

The researchers studied the genes in tumours from 4,086 patients and found 592 significant DNA amplifications in 438 cancer patients, suggesting that 5-10% of cancer patients might be suitable for treatment with an existing targeted therapy. In addition to brain and breast cancers, they found significant amplifications in cancer of the colon (5.8%), lung (5.8%), ovary (4%) and pancreas (3%). They were rare or non-existent in liver cancer, leukaemia and myeloma. As might be expected, amplifications of the HER2 gene were found in breast cancer (13.7% frequency), at which the drug trastuzumab is targeted, but it was also found in small subsets of colorectal (1.3%) and lung (0.9%) cancer patients. There were examples of other gene amplifications occurring in cancers other than those for which targeted therapies had been tested and approved.

The researchers also checked whether the amplifications were ones that were responsible for driving the growth of the various cancers. "We cannot be sure that in each case the DNA amplifications we studied were 'drivers' of cancer, but we can look for clues that the genes are likely to be the drivers," explained Dr Rhodes. "If the amplifications involved small, focal regions of the genome that included only the target or only a few genes, then it is more likely that the target gene was a 'driver'. Also, if the target gene was more frequently amplified and amplified at higher levels than neighbour genes, then again it is more likely that the target gene is the 'driver'. Thus, we examined the regions of amplification around the target genes and the most commonly amplified genes in the region and in almost all cases, our target gene under study was the most commonly and most highly amplified gene in the region."

Dr Rhodes concluded: "We envision our work motivating a DNA amplification-guided clinical trial that would test advanced cancer patients for DNA amplification of all relevant targets and then partition patients into treatment arms based on their particular amplification. Such an effort would be costly and could require hundreds of patients; however, our study provides the basis and the frequencies of amplifications that could be expected. We hope that this work will motivate clinicians to consider such an approach."

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] This study was conducted and funded by Compendia Bioscience.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by ECCO-the European CanCer Organisation, via EurekAlert!, a service of AAAS.

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In Fending Off Diseases, Plants and Animals Are Much the Same, Research Shows

Contrary to long-held beliefs, plants and animals have developed remarkably similar mechanisms for detecting microbial invasions. This holds promise for the future treatment of infectious diseases in humans.

It may have been 1 billion years since plants and animals branched apart on the evolutionary tree but down through the ages they have developed strikingly similar mechanisms for detecting microbial invasions and resisting diseases.

This revelation was arrived at over a period of 15 years by teams of researchers from seemingly disparate fields who have used classical genetic studies to unravel the mysteries of disease resistance in plants and animals, according to a historical overview that will appear in the Nov. 19 issue of the journal Science.

The report, written by Pamela Ronald, a UC Davis plant pathologist, and Bruce Beutler, an immunologist and mammalian geneticist at The Scripps Research Institute, describes how researchers have used common approaches to tease apart the secrets of immunity in species ranging from fruit flies to rice. It also forecasts where future research will lead.

"Increasingly, researchers will be intent on harnessing knowledge of host sensors to advance plant and animal health," said Ronald, who was a co-recipient of the 2008 U.S. Department of Agriculture's National Research Initiative Discovery Award for work on the genetic basis of flood tolerance in rice.

"Some of the resistance mechanisms that researchers will discover will likely serve as new drug targets to control deadly bacteria for which there are currently no effective treatments," she said.

At the heart of this research saga are receptors -- protein molecules usually found on cell membranes -- that recognize and bind to specific molecules on invading organisms, signaling the plant or animal in which the receptor resides to mount an immune response and fend off microbial infection and disease.

Beutler and Ronald have played key roles in this chapter of scientific discovery. In 1995, Ronald identified the first such receptor -- a rice gene known as known as Xa21 -- and in 1998, Beutler identified the gene for the first immune receptor in mammals -- a mouse gene known as TLR4.

Their overview in Science includes illustrated descriptions of the disease-resistance or immunity pathways in the mouse, Drosophila fruit fly, rice and a common research plant known as Arabidopsis. These represent the immune defense systems of vertebrates, insects, monocotyledons (grass-like plants) and dicotyledons (plants like beans that have two seed leaves.)

The researchers note that plant biologists led the way in discovering receptors that sense and respond to infection. The 1980s brought about an intense hunt for the genes that control production of the receptor proteins, followed by an "avalanche" of newly discovered receptor genes and mechanisms in the 1990s.

Another milestone included discovery in 2000 of the immune receptor in Arabidopsis known as FLS2 -- which demonstrated that a plant receptor could bind to a molecule that is present in many different microbial invaders.

The review also discuses how plant and animal immune responses have evolved through the years and which mechanisms have remained the same.

While the past 15 years have been rich in significant discoveries related to plant and animal immunity, Beutler and Ronald are quick to point out that researchers have just scratched the surface.

"If you think of evolution as a tree and existing plant and animal species as the leaves on the tips of the tree's branches, it is clear that we have examined only a few of those leaves and have only a fragmentary impression of what immune mechanisms exist now and were present in the distant past," said Beutler, an elected member of the U.S. National Academy of Sciences.

He and Ronald predict that, as results from new gene sequencing projects become available, scientists will likely find that some plant and animal species emphasize specific resistance mechanisms while having little use for others.

For example, the researchers point out that the Drosophila's immune system depends on only one immunologically active receptor, known as the Toll receptor, to sense invasion by fungi and gram-positive bacteria. In contrast, Arabidopsis has dozens of sensors to protect against microbial infections and rice has hundreds.

Ronald and Beutler project that many surprises will be uncovered by future research as it probes the disease-resistance mechanisms of other species.

The review study was supported with funding from the National Institutes of Health.

Journal Reference:

1. Pamela C. Ronald and Bruce Beutler. Plant and Animal Sensors of Conserved Microbial Signatures. Science, 19 November 2010: Vol. 330 no. 6007 pp. 1061-1064 DOI: 10.1126/science.1189468

Courtesy: ScienceDaily

Courtesy: ScienceDaily

E. Coli Infection Linked to Long-Term Health Problems

People who contract gastroenteritis from drinking water contaminated with E. coli are at an increased risk of developing high blood pressure, kidney problems and heart disease in later life, finds a study published on the British Medical Journal website.

The findings underline the importance of ensuring a safe food and water supply and the need for regular monitoring for those affected.

It is estimated that E. coli O157:H7 infections cause up to 120,000 gastro-enteric illnesses annually in the US alone, resulting in over 2,000 hospitalisations and 60 deaths. However, the long term health effects of E. coli infection in adults are largely unknown.

So a team of researchers in Canada assessed the risk for hypertension, renal impairment and cardiovascular disease within eight years of gastroenteritis from drinking contaminated water.

They used data from the Walkerton Health Study -- the first study to evaluate long term health after an outbreak of gastroenteritis in May 2000 when a municipal water system became contaminated with E. coli O157:H7 and Campylobacter bacteria.

Study participants were surveyed annually and underwent a physical examination and laboratory assessment to track their long term health.

Of 1,977 adult participants, 1,067 (54%) experienced acute gastroenteritis of whom 378 sought medical attention.

Compared with participants who were not ill or only mildly ill during the outbreak, participants who experienced acute gastroenteritis were 1.3 times more likely to develop hypertension, 3.4 times more likely to develop renal impairment, and 2.1 times more likely to have a cardiovascular event, such as a heart attack or stroke.

The authors conclude: "Our findings underline the need for following up individual cases of food or water poisoning by E. coli O157:H7 to prevent or reduce silent progressive vascular injury."

They add: "These long term consequences emphasise the importance of ensuring safe food and water supply as a cornerstone of public health."

Journal Reference:

1. W. F. Clark, J. M. Sontrop, J. J. Macnab, M. Salvadori, L. Moist, R. Suri, A. X. Garg. Long term risk for hypertension, renal impairment, and cardiovascular disease after gastroenteritis from drinking water contaminated with Escherichia coli O157:H7: a prospective cohort study. BMJ, 2010; 341 (nov17 2): c6020 DOI: 10.1136/bmj.c6020

Courtesy: ScienceDaily

New Target Identified for Stopping Tumors Developing Their Own Blood Supply

Researchers have found that a newly developed drug, which is aimed at a particular receptor involved in the development of blood vessels that sustain tumour growth, is active in patients with advanced cancers and, in some cases, has halted the progress of the disease. The drug, ACE-041, targets a different molecular pathway to other anti-angiogenesis drugs and may provide a new option to treat cancer.

Results from a phase I clinical study of ACE-041 were presented at the 22nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin on November 19. The drug targets a receptor known as activin receptor-like kinase-1 (ALK-1), which regulates the formation of new networks of blood vessels needed for tumour growth -- a process known as angiogenesis. While existing anti-angiogenic drugs such as bevacizumab, sunitinib and sorafenib target other angiogenesis receptors such as VEGF, ACE-041 is one of the first to target the ALK-1 pathway.

Professor Sunil Sharma, the Jon and Karen Huntsman Presidential Professor of Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City (USA), told the meeting that the connection of ALK-1 with angiogenesis was made with the discovery that mutations in the ALK-1 gene caused a condition known as hereditary haemorrhagic telangiectasia 2 (HHT2), which is characterised by impaired formation of capillary beds and causes red markings on the skin.

Acceleron Pharma, a biotechnology company in Cambridge, Massachusetts (USA), designed ACE-041 to inhibit ALK-1 signalling and asked Prof Sharma to be one of the investigators to conduct the first-in-man phase I clinical trial of the drug to see if it would inhibit tumour angiogenesis.

"Since ALK-1 is only transiently expressed on proliferating endothelial cells (the cells that line the inner surface of blood vessels), in contrast to the VEGF receptors which are constitutively expressed on endothelial and other cells, it may be a more selective target for the inhibition of angiogenesis," said Prof Sharma. "ALK-1 expression on tumour vasculature has been noted on tumour biopsy samples from a wide range of tumour types."

The phase I study enrolled patients with a range of advanced solid tumours that had spread to other parts of the body or that were inoperable, such as multiple myeloma, non-small cell lung cancer (NSCLC), head and neck cancers and carcinoid tumours (carcinoma-like neuroendocrine tumours that typically originate in the small intestine or appendix). Most patients had been treated unsuccessfully with a range of other treatments, including anti-VEGF drugs, before joining the trial. They were treated as out-patients and ACE-041 was given via subcutaneous injection.

"As of early September, 25 patients have been enrolled in the study, and we have escalated from the starting ACE-041 dose level of 0.1 mg/kg up to 4.8 mg/kg. One patient with head and neck cancer had a partial response, three patients have had stable disease and several other patients have had strongly positive responses as shown by FDG-PET scans. So far, ACE-041 has been well tolerated, with the most common adverse events being peripheral oedema, fatigue, anaemia, headache and nausea," said Prof Sharma.

"It has been very encouraging to see so many signals of efficacy in this trial, in particular because of the study population. These are end-stage cancer patients, who have already been treated with and become refractory to multiple lines of standard therapy. It has also been encouraging to see signals of ACE-041 activity in a wide range of tumour types, since this aligns with our hypothesis that ACE-041 may have anti-tumour activity in any tumour that has angiogenic activity, regardless of tumour histology. It is also important to note that while we have demonstrated significant activity with ACE-041 monotherapy in this study, we might expect to see even more efficacy in future studies with ACE-041 used in combination with other therapies."

Prof Sharma and his colleagues are planning further investigations of the safety and tolerability of the drug in an additional group of patients and hope to start phase II studies of ACE-041 in 2011.

"The anti-VEGF angiogenesis inhibitors, including bevacizumab, sunitinib and sorafenib, have been an important addition to the armamentarium of anti-cancer therapies," said Prof Sharma. "However, their efficacy is somewhat limited since tumours eventually develop the ability to stimulate angiogenesis with non-VEGF angiogenic factors. They also have serious side-effects that arise from effects on blood vessels in normal tissues. Since ACE-041 inhibits angiogenesis in a completely different way, it may have synergistic efficacy with VEGF-inhibitors, and be effective in patients who have developed resistance to VEGF-inhibitors."

Notes

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] This study was funded by Acceleron Pharma Inc.

Courtesy: ScienceDaily

Researchers Unlock a Secret of Bacteria's Immune System

Researchers in France have uncovered a mechanism which explains how biological clocks accurately synchronize to the day/night cycle despite large fluctuations in light intensity during the day and from day to day. Following the identification of two central "clock genes" of a green alga, Ostreococcus tauri, a mathematical model reproducing their daily activity profiles has revealed that their internal clock is influenced by the naturally varying light levels throughout the day only at periods when it needs resetting.

The results found by the biologists at Oceanologic Observatory of Université Paris 6 in Banyuls, France, physicists at Université Lille 1, France, together with the Centre National de la Recherche Scientifique, are published November 11 in the open-access journal PLoS Computational Biology.

Circadian clocks keep track of time in many living organisms, allowing them to anticipate environmental changes induced by day/night alternation. They consist of networks of genes and proteins which interact to generate biochemical oscillations with a period close to 24 hours. Exact synchronization to the day/night cycle requires that some clock components sense daylight. Ostreococcus has evolved a simple but effective strategy to shield the circadian clock from interference caused by fluctuations in the levels of daylight by limiting sensitivity to light to specific times of day. In the authors' model, as in experiments, this ability is furthermore inactivated when the clock is in phase with the day/night cycle but resets the clock when it is out of phase. Such a clock architecture is immune to strong daylight fluctuation such as due to cloud cover.

Light sensing is assumed to be activated only when the core oscillator controlling the biological clock is blind to perturbations and variations. As anyone who has pushed a swing knows, the response of a periodic motion to a perturbation depends indeed very much on the timing; pushing a swing mid-arc doesn't achieve much. With this simple trick, the clock is insensitive to light and its fluctuations when it is on time. However, if the clock becomes out of phase, it will be subjected to light at a different time of its cycle, and respond to the perturbation so as to be reset to the correct time.

Funding: This work has been supported by ANR grant 07BSYS004 to F.-Y.B. and M.L., by CNRS interdisciplinary programme "Interface Physique, Biologie et Chimie : soutien à la prise de risque" to M.L., as well as by Ministry of Higher Education and Research, Nord-Pas de Calais Regional Council and FEDER through the Contrat de Projets État-Région (CPER) 2007-2013.

Journal Reference:

1. Thommen Q, Pfeuty B, Morant P-E, Corellou F, Bouget F-Y, et al. Robustness of Circadian Clocks to Daylight Fluctuations: Hints from the Picoeucaryote Ostreococcus tauri. PLoS Comput Biol, 6(11): e1000990 DOI: 10.1371/journal.pcbi.1000990

Courtesy: ScienceDaily

Keeping the Daily Clock Ticking in a Fluctuating Environment: Hints from a Green Alga

Researchers in France have uncovered a mechanism which explains how biological clocks accurately synchronize to the day/night cycle despite large fluctuations in light intensity during the day and from day to day. Following the identification of two central "clock genes" of a green alga, Ostreococcus tauri, a mathematical model reproducing their daily activity profiles has revealed that their internal clock is influenced by the naturally varying light levels throughout the day only at periods when it needs resetting.

Researchers in France have uncovered a mechanism which explains how biological clocks accurately synchronize to the day/night cycle despite large fluctuations in light intensity during the day and from day to day. Following the identification of two central "clock genes" of a green alga, Ostreococcus tauri, a mathematical model reproducing their daily activity profiles has revealed that their internal clock is influenced by the naturally varying light levels throughout the day only at periods when it needs resetting.

Journal Reference:

1. Thommen Q, Pfeuty B, Morant P-E, Corellou F, Bouget F-Y, et al. Robustness of Circadian Clocks to Daylight Fluctuations: Hints from the Picoeucaryote Ostreococcus tauri. PLoS Comput Biol, 6(11): e1000990 DOI: 10.1371/journal.pcbi.1000990

Courtesy: ScienceDaily

New DNA Repair Pathway

UC Davis researchers have found a new pathway for repairing DNA damaged by oxygen radicals. The results are published this week in the journal Proceedings of the National Academy of Sciences.

"This new inducible pathway gives cells greater capacity to repair oxidative damage," said Peter Beal, professor of chemistry at UC Davis and senior author of the paper.

As part of its inflammatory response, the body's immune system produces oxygen radicals, or reactive oxygen species, to kill bacteria, parasites or tumors. But chronic inflammation, for example in the gut, has been linked to cancer, said co-author Professor Sheila David, also of the Department of Chemistry.

Oxygen radicals are strongly linked to cancer and aging and are also formed during metabolism and upon exposure to environmental toxins and radiation. Understanding more about how this damage can be repaired could lead to a better understanding of the causes of some cancers.

Oxygen radicals can react with the four bases that make up the "letters" of DNA -- A, C, G and T -- so that the "spelling" of genes gets changed. The accumulation of spelling errors (called mutations) can lead to cancer.

David's laboratory studies an enzyme called NEIL1 that detects and repairs these aberrant or damaged bases before changes in the genome become permanent.

Beal's group works on RNA editing. The first step in turning a gene into a protein is to make a copy of the DNA in RNA. This messenger RNA is then translated into the chain of amino acids that makes up a protein. In some cases, this RNA is "edited" between the transcription from DNA and the translation into protein.

At a conference last year, Beal -- who happens to be David's husband -- spotted NEIL1 among a list of genes that had just been discovered to be subject to RNA editing, and passed the news on to David.

On investigation, they found that NEIL1's messenger RNA is edited by an enzyme called ADAR1. In that editing, one of the chains of amino acids that make up NEIL1 changes from lysine to arginine, causing a slight, but noticeable, change in the structure of the protein.

Using a cell line derived from nerve cells, the team found no editing of NEIL1 RNA in resting cells. But when the cells were treated with interferon, which is produced during inflammation and to fight off viruses, the cells started making ADAR1 and editing NEIL1.

"The interferon-treated cells had two forms of the NEIL1 protein, one with lysine and one with arginine," Beal said.

NEIL1 can fix a number of different damaged DNA bases that form when normal DNA bases are attacked by oxygen radicals. Beal and David found that the two different forms of NEIL1 had different abilities to act upon the damaged DNA bases: the basic, lysine version had a broader range but lower activity, while the edited, arginine form had higher activity but was effective against a more limited range of targets. That might give the cell more flexibility in responding to DNA damage.

Beal and David believe that the whole system works something like this: Inflammation creates oxygen radicals, which damage DNA, which is repaired by NEIL1. Inflammation also generates interferon, which induces ADAR1, which then edits NEIL1 to produce the more active, specific form to cope with more severe types of DNA base damage.

The other co-authors on the paper are Jongchan Yeo, Rena Goodman and Nicole Schirle, all graduate students in the Department of Chemistry. The work was supported by grants from the National Institute for General Medical Sciences and the National Cancer Institute, both parts of the National Institutes of Health.

Journal Reference:

1. Jongchan Yeo, Rena A. Goodman, Nicole T. Schirle, Sheila S. David, Peter A. Beal. RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1009231107

Courtesy: ScienceDaily

Redeeming Role for a Common Virus: Ability to Kill Cancer

A common virus that can cause coughing and mild diarrhea appears to have a major redemptive quality: the ability to kill cancer. Harnessing that power, researchers at Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center, are conducting a clinical trial to see if the virus can target and kill certain tumor types.

By the age of five, most people have been exposed to the virus, called reovirus. For some, it can trigger brief episodes of coughing or diarrhea while many other don't develop any symptoms. The body simply overpowers the virus. But what scientists have discovered is that the virus grows like gangbusters inside tumor cells with a specific malfunction that leads to tumor growth. That finding led researchers to ask: Is it possible to use the virus as a treatment?

At Lombardi, researchers are collaborating with other institutions to look for an answer by conducting a phase II clinical trial for people with advanced or recurrent non-small cell lung cancer with a specific tumor profile.

"With reovirus, we're able to accentuate the positive and attenuate the negative," says the study's lead investigator at Lombardi, Deepa Subramaniam, MD, interim-chief of the Thoracic Medical Oncology Program. In other words, researchers have genetically altered the virus so that it won't replicate in a healthy cell (attenuated), which is what makes a person sick. "What's left is a virus in search of a host, and reovirus loves the environment inside a specific kind of cancer cell," explains Subramaniam.

That specific kind of cancer cell is one with malfunctioning machinery called KRAS or EGFR mutation.

"These mutations leave the cancer vulnerable to a viral take-over. Once it's in, the reovirus exploits the cell's machinery to drive its own replication. As a result, the cell is filled with virus particles causing it to literally explode."

Volunteers in the clinical trial will receive reovirus (REOLYSIN®) in addition to paclitaxel and carboplatin. The physicians will watch to see if the cancer shrinks while also seeing if this combination of drugs causes serious side effects.

"This is a subset of cancer where we haven't had many successes in terms of finding drugs that extend life after diagnosis," says Subramaniam. "This trial represents an attempt to seek and destroy cancer by choosing a treatment based on specific tumor characteristics. Preliminary data from the study should come quickly."

Researchers are also studying the effect of reovirus in other cancer types.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Georgetown University Medical Center, via EurekAlert!, a service of AAAS.

Courtesy: ScienceDaily

'Nano-Drug' Hits Brain-Tumor Target: Unique Triggering Device Delivers Antitumor Drugs

Nine years ago, scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute detected a subtle shift occurring in the molecular makeup of the most aggressive type of brain tumors, glioblastoma multiforme. With further study, they found that a specific protein called laminin-411 plays a major role in a tumor's ability to build new blood vessels to support its growth and spread. But technology did not exist then to block this protein.

Now, employing new drug-engineering technology that is part of an advanced science called nanomedicine, the research team has created a "nanobioconjugate" drug that may be given by intravenous injection and carried in the blood to target the brain tumor. It is engineered to specifically permeate the tumor cell wall, entering endosomes, mobile compartments within cells.

As endosomes mature, they grow acidic (low pH), and a chemical component of the drug triggers at this point, breaking the endosomes' membranes. Freed drugs block the tumor cell's production of laminin-411, the "malignant" protein of new tumor vessels. By its nature, the drug is nontoxic to non-tumor cells; side effects associated with conventional chemotherapy are not an issue with this class of drugs.

This approach is believed to be the first of its kind -- the first application of a pH-dependent endosome escape unit in drugs administered intravenously for brain cancer treatment -- as reported in Proceedings of the National Academy of Sciences (online). Studies in lab mice show this system allows large amounts of antitumor drug to accumulate in tumors, significantly slowing the growth of new vessels and the tumors themselves. Tumors in animals treated with the drug were 90 percent smaller than those in a control group.

Gliomas, a type of malignant brain tumors, are extremely difficult to treat. Their tendency to spread into healthy brain tissue and their ability to reappear in distant locations make them virtually impossible to surgically remove completely. They resist chemotherapy and radiation therapy, and the brain itself is "protected" by the blood-brain barrier and immune system mechanisms that thwart most therapies.

The system developed at Cedars-Sinai -- a nanobioconjugate -- appears to clear major hurdles to brain tumor drug treatment. Nanoconjugates are the latest evolution of molecular drugs designed to enter cells and specifically alter defined targets within them. As suggested by the term "bioconjugate," these systems contain chemical "modules" attached (conjugated) to a delivery vehicle by strong chemical bonds. Such bonds prevent the components from being damaged or separated in tissues or blood plasma during transit. But with inventive drug engineering, the antitumor component activates directly inside tumor cells.

A nanoconjugate exists as a single chemical unit, with its components performing critical tasks in a predetermined sequence and attacking several targets simultaneously. The ultimate assault on a tumor cell depends on a complex, well-choreographed chain of biochemical events, such as: penetrating the blood-brain barrier and the blood-brain tumor barrier; specifically homing to tumor cells; permeating the walls of blood vessels and tumor cells; releasing antitumor drugs at the right place and time; and dismantling mechanisms that help tumor-feeding blood vessels grow.

"This nanobioconjugate is different from earlier nanomedicine drugs because it delivers and releases antitumor drugs within tumor cells, not just at the site of a tumor," said research scientist Julia Y. Ljubimova, M.D., Ph.D., senior author of the article. She directs the Drug Delivery and Nanomedicine Laboratory in the Department of Neurosurgery at Cedars-Sinai. Other major contributors to this study and the article include: Hui Ding, Ph.D., and Eggehard Holler, Ph.D., chemists, biochemists and immunologists. Holler is affiliated with both Cedars-Sinai and the University of Regensburg in Germany.

Cedars-Sinai's drug, a macromolecule of 20 to 30 nanometers in size, is based on a highly purified form of polymalic acid derived from the single cell organism Physarum polycephalum. When the nanoconjugate has accomplished its tasks, the body digests it completely, leaving no harmful residue.

"Based on our studies, this nanoconjugate appears to be a safe and efficient delivery platform that also may be appropriate in the treatment of degenerative brain conditions and a wide array of other disorders. It is harmlessly degraded to carbon dioxide and water, nontoxic to normal tissue, and, unlike some drugs, it is non-immunogenic, meaning that it does not stimulate the immune system to the point of causing allergic reactions that can range from mild coughs or rashes to sudden, life-threatening symptoms," Ljubimova said. Researchers anticipate that human clinical trials of the drug will begin in the near future.

Journal Reference:

1. H. Ding, S. Inoue, A. V. Ljubimov, R. Patil, J. Portilla-Arias, J. Hu, B. Konda, K. A. Wawrowsky, M. Fujita, N. Karabalin, T. Sasaki, K. L. Black, E. Holler, J. Y. Ljubimova. Inhibition of brain tumor growth by intravenous poly( -L-malic acid) nanobioconjugate with pH-dependent drug release. Proceedings of the National Academy of Sciences, 2010; 107 (42): 18143 DOI: 10.1073/pnas.1003919107

Courtesy: ScienceDaily

Breakthrough in Cancer Vaccine Research

Researchers at the University of Cambridge hope to revolutionise cancer therapy after discovering one of the reasons why many previous attempts to harness the immune system to treat cancerous tumours have failed.

New research, published November 4 in the journal Science, reveals that a type of stromal cell found in many cancers which expresses fibroblast activation protein alpha (FAP), plays a major role in suppressing the immune response in cancerous tumours -- thereby restricting the use of vaccines and other therapies which rely on the body's immune system to work. They have also found that if they destroy these cells in a tumour immune suppression is relieved, allowing the immune system to control the previously uncontrolled tumour.

Douglas Fearon, Sheila Joan Smith Professor of Immunology of the Department of Medicine at the University of Cambridge, said: "Finding the specific cells within the complex mixture of the cancer stroma that prevents immune killing is an important step. Further studying how these cells exert their effects may contribute to improved immunological therapies by allowing us to remove a barrier that the cancer has constructed."

Vaccines created to prompt the immune system to attack cancerous cells in tumours have shown to activate an immune response in the body but have, inexplicably, almost never affected the growth of tumours. Immunologists who specialise in tumours have suspected that within the tumour microenvironment the activity of immune cells is somehow suppressed, but they have thus far been unable to fully reverse this suppression.

The new research, funded by the Wellcome Trust and the Sheila Joan Smith Professorship endowment, sheds light on why the immune response is suppressed. The Cambridge study found that at least one immune suppressive component is contained within normal tissue cells (called stromal cells) the cancer has coerced to assist its survival. The cell they studied specifically expresses a unique protein often associated with wound healing -- fibroblast activation protein alpha (FAP). The FAP expressing cells are found in many cancers, including breast and colorectal cancers.

In order to determine if FAP expressing stromal cells contribute to the resistance of a tumour to vaccination, the researchers created a transgenic mouse model which allowed them to destroy cells which expressed FAP. When FAP-expressing cells were destroyed in tumours in mice with established Lewis lung carcinomas (of which only 2% of the tumour cells are FAP-expressing), the cancer began to rapidly 'die'. The Fearon lab now hopes to collaborate with scientists at the CRUK Cambridge Research Institute to evaluate the effects of depleting FAP-expressing cells in a mouse model that more closely resemble human cancer, and to examine FAP-expressing cells of human tumours.

Professor Fearon continued: "These studies are in the mouse, and although there is much overlap between the mouse and human immune systems, we will not know the relevance of these findings in humans until we are able to interrupt the function of the tumour stromal cells expressing FAP in patients with cancer.

"It should be noted, however, that the FAP-expressing stromal cell was actually first found in human cancer by Lloyd Old and his colleagues 20 years ago."

Journal Reference:

1. Matthew Kraman, Paul J. Bambrough, James N. Arnold, Edward W. Roberts, Lukasz Magiera, James O. Jones, Aarthi Gopinathan, David A. Tuveson, and Douglas T. Fearon. Suppression of Antitumor Immunity by Fibroblast Activation Protein -- α -- Expressing Stromal Cells. Science, November 5 2010 330: 827-830 DOI: 10.1126/science.1195300

Courtesy: ScienceDaily

Luminous Cells from Jellyfish Could Diagnose Cancers Deep Within Human Body

Scientists in Yorkshire have developed a process that uses the luminous cells from jellyfish to diagnose cancers deep within the human body.

The method has been developed at the Yorkshire Cancer Research Laboratory at The University of York and the man who leads the York team, Professor Norman Maitland, believes it will revolutionize the way some cancers are diagnosed.

"Cancers deep within the body are difficult to spot at an early stage, and early diagnosis is critical for the successful treatment of any form of cancer," he said. "What we have developed is a process which involves inserting proteins derived from luminous jellyfish cells into human cancer cells. Then, when we illuminate the tissue, a special camera detects these proteins as they light up, indicating where the tumors are."

The process is an extension of the work done by American chemist Dr. Roger Y. Tsien, who won a Nobel Prize in 2008 for taking luminous cells from a common jellyfish called the crystal jelly and isolating the green fluorescent protein (GFP). The GFP is the substance that allows jellyfish to glow in the dark.

"When we heard about Dr. Tsien's work, we realized how that advance might be useful in the diagnosis of cancer," said Prof. Maitland. "X-Rays, for example, struggle to penetrate well deeply into tissues and bone, so diagnosing dangerous microscopic bone cancer is difficult. Our process should allow earlier diagnosis to take place."

What the Yorkshire Cancer Research team has done is to use an altered form of the protein so that it shows up as red or blue, rather than its original green. Color is important for these tests, as most colors in the spectrum are rapidly absorbed, and tumors deep within the body become invisible. You can try this for yourself by shining a torch light through your hand -- the only color which you can see is red.

In the procedure, viruses containing the proteins are targeted to home in on tiny bundles of cancer cells scattered throughout the body (metastases). Normally, this would not be enough to see the minute tumors, which are too small to be seen by conventional scanning techniques. But the viruses then start to grow, and while doing so make more of the red fluorescent proteins.

Thousands of copies are made in each cancer cell, a process, which is repeated in the surrounding cells, as the virus infection spreads and then stops.

"When a specially developed camera is switched on, the proteins just flare up and you can see where the cancer cells are." said Prof. Maitland, "We call the process 'Virimaging' ."

If the research continues to go according to plan, the method is expected to be ready for clinical trials within five years and could be ready for diagnostic use by clinicians a few years after this. It has to be tested thoroughly, as a failure to detect such small cancers has serious consequences for patients.

However, while the system works in the laboratory, one major hurdle is a shortage of specialized cameras.

Only one company, based in the United States, has so far designed and built a camera system which allows the jellyfish proteins to be seen with the desired resolution deep in the body. The camera costs around half a million pounds, and Prof. Maitland is currently raising the funds to be able to buy one.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Yorkshire Cancer Research.

Courtesy: ScienceDaily

Hard Work Improves the Taste of Food, Study Shows

It's commonly accepted that we appreciate something more if we have to work hard to get it, and a Johns Hopkins University study bears that out, at least when it comes to food.

The study seems to suggest that hard work can even enhance our appreciation for fare we might not favor, such as the low-fat, low calorie variety. At least in theory, this means that if we had to navigate an obstacle course to get to a plate of baby carrots, we might come to prefer those crunchy crudités over sweet, gooey candy bars more easily accessible via the office vending machine.

"Basically, what we have shown is that if you have to expend more effort to get a certain food, not only will you value that food more, but it might even taste better to you," explained Alexander Johnson, an associate research scientist in the Department of Psychological and Brain Sciences at the Krieger School of Arts and Sciences at Johns Hopkins. "At present, we don't know why effort seems to boost the taste of food, but we know that it does, and this effect lasts for at least 24 hours after the act of working hard to get the food."

The study, titled "Greater effort boosts the affective taste properties of food," appears in this week's issue of the Proceedings of the Royal Society B.

The study results are significant not only because they hold out hope that people who struggle to maintain a healthy weight could be conditioned to consume lower calorie foods, but because they also might provide insight into methods of altering other less-than-optimal behavior, according to Johnson, who led the study.

Johnson teamed up on the project with Michela Gallagher, the Krieger-Eisenhower Professor of Psychological and Brain Sciences and Neuroscience and vice provost for academic affairs at Johns Hopkins. Using ordinary laboratory mice, the team conducted two experiments.

In the first, mice were trained to respond to two levers. If the mice pressed one lever once, they were rewarded with a sugary treat. Another lever had to be pressed 15 times to deliver a similar snack. Later, when given free access to both tidbits, the rodents clearly preferred "the food that they worked harder for," Johnson said.

In the second experiment, the team wanted to ascertain whether the animals' preference for the harder-to-obtain food would hold if those morsels were low-calorie. So half the mice received lower calorie goodies from a high-effort lever, and half got them from a low-effort lever. When both groups of mice were given free access to the low-calorie food later, those who had used the high-effort lever ate more of it and even seemed to enjoy it more than did the other group.

"We then analyzed the way in which the mice consumed the food," Johnson explained. "Why did we do this? Because food intake can be driven by a variety of factors, including how it tastes, how hungry the mice were beforehand, and how 'sated' or full the food made them feel."

Johnson and Gallagher used licking behavior as a measure of the rodents' enjoyment of their treats, and found that the mice that had to work harder for their low-cal rewards did, in fact, savor them more.

"Our basic conclusion is that under these conditions, having to work harder to get a certain food changes how much that food is valued, and it does that by changing how good that food tastes," Johnson said. "This suggests that, down the road, obese individuals might be able to alter their eating habits so as to prefer healthier, low calorie food by manipulating the amount of work required to obtain the food. Of course, our study didn't delve into that aspect. But the implications certainly are there."

The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Mental Health.

Journal Reference:

1. A. W. Johnson, M. Gallagher. Greater effort boosts the affective taste properties of food. Proceedings of the Royal Society B: Biological Sciences, 2010; DOI: 10.1098/rspb.2010.1581

Courtesy: ScienceDaily

Newly Discovered Gene Enables Fish to 'Disappear'

Researchers led by Vanderbilt's Roger Cone, Ph.D., have discovered a new member of a gene family that has powerful influences on pigmentation and the regulation of body weight.The gene is the third member of the agouti family. Two agouti genes have been identified previously in humans. One helps determine skin and hair color, and the other may play an important role in obesity and diabetes.

The new gene, called agrp2, has been found exclusively in bony fish, including zebrafish, trout and salmon. The protein it encodes enables fish to change color dramatically to match their surroundings, the researchers report this week in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

"When my graduate student, Youngsup Song, discovered a third agouti protein in the fish pineal gland, an organ that regulates daily rhythms in response to light, we initially thought we had found the pathway that regulates hunger diurnally," said Cone, chair of the Department of Molecular Physiology & Biophysics and director of the Vanderbilt Institute for Obesity and Metabolism.

"That is the mechanism that makes you hungry during the day, but not at night," he continued. "However, Chao Zhang, a graduate student who followed up the study, ultimately discovered that this agouti protein … is involved in the rapid pigment changes that allow fish to adapt to their environment."

This phenomenon, called background adaptation, also has been observed in mammals. The coat of the arctic hare, for example, turns from brown in summer to white camouflage against the winter snow.

In contrast to mammals that have to grow a new coat to adapt to a changing environment, fish, amphibians and reptiles can change their skin color in a matter of minutes.

The first agouti gene, which produces the striped "agouti" pattern in many mammals, was discovered in 1993. The same year, Cone and his colleagues at Oregon Health Sciences University in Portland reported the discovery of the gene that encoded the melanocortin-1 receptor, a key player in the pigmentation story.

They demonstrated that the agouti protein prevented the melanocortin-1 receptor in melanocytes (pigment cells) in the skin from switching on production of black-brown pigment, and instead shifted the pigment to yellow-red hues.

The second agouti gene encodes agouti-related protein (AgRP), which blocks a melanocortin receptor in the brain. It prevents the melanocortin-4 receptor from inhibiting food intake, and thus stimulates eating.

In the current paper, Cone's group reports that the newly discovered protein, AgRP2, regulates expression of the prohormone genes pmch and pmchl, precursors to melanin-concentrating hormone, which has a pigment-lightening effect.

"Together, the versatile agouti proteins and melanocortin receptors are responsible for regulation of body weight, the banded patterns of mammalian coats, and even red hair in most people," Cone said. The current work shows that agouti proteins are also involved in the camouflage mechanisms used in thousands of fish species.

Cone, who came to Vanderbilt in 2008, has spent most of his career studying how the melanocortin receptors in the brain regulate body weight. He and his colleagues have published more than three dozen papers elucidating elements of this complex signaling system.

Zhang is the first author of the PNAS paper, a collaborative effort of scientists from the Salk Institute for Biological Sciences, the University of California at Santa Cruz, the University of Oregon, as well as Vanderbilt.

Journal Reference:

1. C. Zhang, Y. Song, D. A. Thompson, M. A. Madonna, G. L. Millhauser, S. Toro, Z. Varga, M. Westerfield, J. Gamse, W. Chen, R. D. Cone. Inaugural Article: Pineal-specific agouti protein regulates teleost background adaptation. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1014941107

Courtesy: ScienceDaily

New Test Measures DNA Methylation Levels to Predict Colon Cancer

An investigational DNA methylation test could alter the screening landscape for colorectal cancer, according to data presented at the American Association for Cancer Research special conference on Colorectal Cancer: Biology to Therapy, held in Philadelphia Oct. 27-30, 2010.

Colorectal cancer is the third leading cause of cancer, and the second leading cause of cancer mortality. While celebrities continue to undergo public colonoscopies in an effort to increase awareness, only 60 percent of adults age 50 and older have undergone recommended screening, according to the Centers for Disease Control and Prevention.

David Ahlquist, M.D., professor of medicine and a consultant in gastroenterology at the Mayo Clinic in Rochester, said much of that low rate may be due to inconveniences associated with conventional approaches.

"There is definitely an incentive and legitimate justification to be designing a screening approach that is user friendly, affordable and has the ability to detect pre-cancers," said Ahlquist. "The noninvasive stool DNA test we have developed is simple for patients, involves no diet or medication restriction, no unpleasant bowel preparation, and no lost work time, as it can be done from home. Positive tests results would be followed up with colonoscopy."

The test that Ahlquist and colleagues evaluated is under development by Exact Sciences, a molecular diagnostics company in Wisconsin.

The test, which is not yet approved by the FDA, is conducted using a stool sample and works by detecting tumor-specific DNA alterations in cells that are shed into the stool from pre-cancerous or cancerous lesions.

In this first clinical validation study presented at the AACR conference, which included 1,100 patients, the researchers detected 64 percent of precancerous adenomas greater than 1 cm and 85 percent of cancers. Polyps over 1 cm are considered the most likely to progress. Furthermore, cancers and precancerous adenomas were detected equally well on both sides of the colon.

Colorectal cancer rate detection was 87 percent for cancers considered to be in the most curable stage (stage I-III) and 69 percent for the most advanced stage (stage IV).

Further clinical trials are planned for next year, according to Exact Sciences.

Under an exclusive license agreement with Mayo, Exact has rights to intellectual property developed by Ahlquist and Mayo Clinic. Exact will make up-front, milestone and royalty payments to Mayo Clinic, which will be shared with Ahlquist in accordance with Mayo Clinic's Royalty Sharing Policy and will also provide funding for future work in Ahlquist's lab.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Association for Cancer Research, via EurekAlert!, a service of AAAS.

Courtesy: ScienceDaily

Scientists Uncover Evolution of New Virus, Closely Related to Poliovirus

Scientists at the University of Liverpool have completed the first major review of diagnostic methods and treatments for a rapidly evolving virus that causes hand, foot and mouth disease in children.

The virus, called enterovirus 71, is closely related to poliovirus, and was first detected in California in the 1960s. Since then the virus has spread across Asia, affecting mostly children and some adults. Serious cases of the disease can include neurological disorders such as meningitis, paralysis and encephalitis.

As a result of a global health campaign, polioviruses have almost been eradicated in many areas of the world. Enterovirus 71, however, has caused major outbreaks of hand, foot, and mouth disease and it is still unclear why such a high number of cases occur in the Asia-Pacific region. In the first major review of diagnostic and treatment measures for the disease, the Liverpool team, in collaboration with Universiti Malaysia Sarawak, has revealed that the virus evolves rapidly and is transmitted amongst family members more easily than previously thought.

Professor Tom Solomon, Head of the Institute for Global Health and Infection, explains: "The condition is difficult to diagnose as there are many viruses that can cause hand, foot and mouth disease. It takes time to test all the likely virus samples and identify the cause, so we have now developed a new method to allow scientists to test the most likely samples first and ensure early detection."

Dr Mong How Ooi, who led the study from Malaysia, added: "The biggest challenge to doctors looking after children with this infection is to ascertain if a child could develop serious brain infection. We have produced predicative tests, which include peak temperature measurements and monitoring the duration of fever, as well as looking for signs of lethargy. These assessments allow medics to decide which patients are most at risk from brain infection."

The team analysed current preventative measures, which rely on guidance to families for improving personal and domestic hygiene. It is thought that the virus is most likely spread through faeces, although scientists have now found evidence to suggest it can also be spread through coughing and sneezing.

The review highlighted that more work is needed to understand how effective drug treatments are for the disease. Scientists emphasised that preventative measures, such as the development of vaccines, are the next steps to ensure that the virus does not continue to spread across Asia and other areas of the world.

The research, funded by the Wellcome Trust, is published in two companion articles in the Lancet Infectious Diseases and the Lancet Neurology.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Liverpool.

Courtesy: ScienceDaily