Source: http://pe.com/localnews/inland/stories/…

By DAVID DANELSKI
The Press-Enterprise

Dr. Julia Ljubimova found something disturbing when she probed the brains of rats exposed to air pollution: The dirty air appeared to trigger changes indicating the earliest stage of brain tumors.

Ljubimova, an oncologist and researcher at Cedars-Sinai Medical Center in Los Angeles, stressed that she is not ready to say air pollution is a cause of brain cancer.

“I don’t want to scare anyone, because this is preliminary data,” she said. “But we found something very important.”

Her work suggests that fine particles like those found in diesel soot can switch on the tumor genes that many people inherit, jump-starting the disease process that results in brain tumors.

Hundreds of studies have linked air pollution to early deaths, heart attacks, reduced lung function, lung cancer and various other health problems. Ljubimova is among a handful of scientists who are focused on finding out what air pollution does to people’s brains.

The first results from the fledging research field are creating concern.

In addition to Ljubimova’s work:

A University of Southern California epidemiologist reported to air pollution regulators last year that children living in Southern California’s more polluted areas — including the Inland area — had a higher risk of developing brain tumors.

A UC Irvine toxicologist reported last month at a Society of Toxicology meeting in Seattle that mice exposed to air pollution near the Coliseum sports stadium in central Los Angeles had brain inflammation and cell injuries associated with the first stages of diseases like Alzheimer’s and Parkinson’s.

Last year, Danish researchers monitored brain waves of people exposed to diesel exhaust and found that the pollution increased brain-wave activity, suggesting pollution may alter brain function. Their research was published last month in the journal Particle and Fibre Toxicology.

The findings so far don’t prove that air pollution causes brain disease, “but it is intriguing and worrisome,” Roberta McKean-Cowdin said. She is the USC epidemiologist who analyzed health data to find an apparent correlation between pollution and brain tumors in children from newborns to 5 years of age.

Dr. Keith Black, who is chairman of the Cedars-Sinai neurosurgery department and oversees Ljubimova’s project, hopes the work will lead to discoveries that will allow doctors to prevent or treat the disease. The research also could identify specific particles in diesel exhaust or other pollution that cause cancer, allowing development of engines that don’t emit those particles.

Brain cancer, which can destroy the mind and body simultaneously, killed an estimated 12,700 people in the United States last year.

Black, who has performed more than 7,000 brain cancer surgeries, had seen first-hand the devastation the disease inflicts on victims and their loved ones. It motivated him to pursue research.

“It is a lot easier to prevent the formation of cancer than it is to treat cancer,” he said.

Research Takes Root

The idea for air pollution research at Cedars-Sinai came out of a 2002 Christmas party conversation between Black and William Burke, a 14-year member of the governing board of the South Coast Air Quality Management District, which regulates polluters in Orange County and most populated areas of San Bernardino, Riverside and Los Angeles counties.

They talked about the rise in brain cancer cases among children and how, as studies had shown, firefighters exposed to diesel exhaust in their fire stations were more likely to develop brain cancer than people in other occupations, Black recalled.

At the time, research had shown that the microscopic particles of pollution could work their way through blood vessel walls and enter the brain, an organ normally protected from such invasions.

Burke took the conversation seriously.

“That was something we needed to we know more about right away,” he said.

In 2003, Burke persuaded his colleagues to form the Brain and Lung Tumor and Air Pollution Foundation to fund research. Using money the South Coast district collects through fines on polluters, the foundation so far has provided about $2.1 million to molecular biology work at Cedars-Sinai and $178,000 to USC to examine brain cancer incidence among people living polluted areas, including the Inland region.

Burke said he plans to ask the board this year to dedicate 5 to 10 percent of future fine revenues to such research. The amounts vary, but the air district expects to collect about $4.1 million in fines this fiscal year.

Genes and Pollution

Ljubimova, a native of Azerbaijan and daughter of a Soviet military doctor, studied medicine in Kiev, Ukraine. She treated cancer patients in Moscow, then took a research position at Baylor College of Medicine in Houston in 1990. She joined Cedars-Sinai three years later and is now molecular oncology director for the hospital’s Department of Neurosurgery.

She has probed the biochemistry of breast and liver cancer in a quest for better treatments and cures. She now focuses on the genetic mechanisms involved in brain and breast tumors.

Thousands of genes within the DNA of a cell carry the instructions to build every component of an organism’s life. A gene contains blueprints to build the proteins, for example, that allow a red blood cell to carry oxygen and distribute it through the body. Other genes determine eye and hair color, height and whether a person will tend to be fat or thin.

Some genes contain instructions to grow cells that compose deadly tumors. If such genes become active, cancer forms.

To test how fine particles affect the brain, Ljubimova divided about 180 laboratory rats into groups and exposed them to three sizes of pollution particles for periods ranging from two weeks to 10 months. The rats were subjected to air many times more polluted than the air Southern Californians breathe.

After each exposure period, the rats were euthanized and their brain tissue examined for gene activity.

In the pollution-exposed rats, the genes associated with brain tumors were more active than in the rats that breathed purified air. The same genes are found in human tumor samples collected by the medical center.

The Cedars-Sinai research also found that the longer the rats breathed polluted air, the more active the cancer genes.

The pollution “might trigger or turn on the process or processes for several pathways that transform normal cells into malignant cells,” Ljubimova said.

Her findings will be presented at an international conference in June. The medical center plans to seek grants to continue her investigation, with longer pollution exposures and further analysis to learn why tumor genes are activated.

“We have to do more molecular biology to learn the mechanism,” she said.

Message in the Numbers

Instead of studying rats, USC’s McKean-Cowdin is looking for clues in illnesses that already have happened. She examined records from 496 brain cancer cases among Southern California infants and children between 1991 and 2002.

Her preliminary finding: People living in areas with higher levels of fine-particle pollution have a higher risk for brain cancer. That holds true in the Inland region, she said.

Northwest Riverside County and southwest San Bernardino County regularly exceed federal and state health standards for fine-particle pollution.

McKean-Cowdin said her research is undergoing further analysis and is expected to be published this year in a scientific journal. Her next step, if she can find funding, will to be examine potential links between air pollution and children as old as 19.

Cancer is caused by numerous factors, including genetics and exposure to toxic substances in the environment. Black said.

“It may be air pollution is one of those components,” he said.

Reach David Danelski at 951-368-9471 or

Source: http://usc.edu/uscnews/stories/15032.html

Fasting for two days protects healthy cells against chemotherapy, according to a study appearing online the week of Mar. 31 in PNAS Early Edition.

Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors.

The chemotherapy worked as intended on cancer, extending the lifespan of mice injected with aggressive human tumors, reported a group led by Valter Longo of the University of Southern California.

Test tube experiments with human cells confirmed the differential resistance of normal and cancer cells to chemotherapy after a short period of starvation.

Making chemotherapy more selective has been a top cancer research goal for decades. Oncologists could control cancers much better, and even cure some, if chemotherapy were not so toxic to the rest of the body.

Experts described the study as one of a kind.

“This is a very important paper. It defines a novel concept in cancer biology,” said cancer researcher Pinchas Cohen, professor and chief of pediatric endocrinology at the University of California, Los Angeles.

“In theory, it opens up new treatment approaches that will allow higher doses of chemotherapy. It’s a direction that’s worth pursuing in clinical trials in humans.”

Felipe Sierra, director of the Biology of Aging Program at the National Institute on Aging, said: “This is not just one more anti-cancer treatment that attacks the cancer cells. To me, that’s an important conceptual difference.”

Sierra was referring to decades of efforts by thousands of researchers working on “targeted delivery” of drugs to cancer cells. Study leader Longo focused instead on protecting all the other cells.

Sierra added that progress in cancer care has made patients more resilient and able to tolerate fasting, should clinical trials confirm its usefulness.

“We have passed the stage where patients arrive at the clinic in an emaciated state. Not eating for two days is not the end of the world,” Sierra said.

“This could have applicability in maybe a majority of patients,” said David Quinn, a practicing oncologist and medical director of USC Norris Hospital and Clinics. He predicted that many oncology groups would be eager to test the Longo group’s findings, and advised patients to look for a clinical trial near home.

Longo, an anti-aging researcher who holds joint appointments in gerontology and biological sciences at USC, said that the idea of protecting healthy cells from chemotherapy may have seemed impractical to cancer researchers, because the body has many different cells that respond differently to many drugs.

“It was almost like an idea that was not even worth pursuing. In fact it had to come from the anti-aging field, because that’s what we focus on: protecting all cells at once,” Longo said.

“What really was missing was a perspective of someone from the aging field to give this field a boost,” UCLA’s Cohen said.

The idea for the study came from the Longo group’s previous research on aging in cellular systems, primarily lowly baker’s yeast.

About five years ago, Longo was thinking about the genetic pathways involved both in the starvation response and in mammalian tumors.

When the pathways are silenced, starved cells go into what Longo calls a maintenance mode characterized by extreme resistance to stresses. In essence the cells are waiting out the lean period, much like hibernating animals.

But tumors by definition disobey orders to stop growing because the same genetic pathways are stuck in an “on” mode.

That could mean, Longo realized, that the starvation response might differentiate normal and cancer cells by their stress resistance, and that healthy cells might withstand much more chemotherapy than cancer cells.

The shield for healthy cells does not need to be perfect, Longo said. What matters is the difference in stress resistance between healthy and cancerous cells.

During the study, conducted both at USC and in the laboratory of Lizzia Raffaghello at Gaslini Children’s Hospital in Genoa, Italy, the researchers found that current chemotherapy drugs kill as many healthy mammalian cells as cancer cells.

“(But) we reached a two to five-fold difference between normal and cancer cells, including human cells in culture. More importantly, we consistently showed that mice were highly protected while cancer cells remained sensitive,” Longo said.

If healthy human cells were just twice as resistant as cancer cells, oncologists could increase the dose or frequency of chemotherapy.

“We were able to reach a 1,000-fold differential resistance using a tumor model in baker’s yeast. If we get to just a 10-20 fold differential toxicity with human metastatic cancers, all of a sudden it’s a completely different game against cancer,” Longo said.

“Now we need to spend a lot of time talking to clinical oncologists to decide how to best proceed in the human studies.”

Edith Gralla, a research professor of chemistry at UCLA, said: “It is the sort of opposite of the magic bullet. It’s the magic shield.”

###
Funding from the study came from NIA (part of the National Institutes on Health), the USC Norris Cancer Center and the Associazione Italiana per la Lotta al Neuroblastoma.

USC graduate student Changhan Lee and Gaslini’s Raffaghello performed key experiments. The other authors were Fernando Safdie, Min Wei and Federica Madia of USC, and Giovanna Bianchi of Gaslini.

Longo has been studying aging at the cellular level for 15 years, and has published in the nation’s leading scientific journals. He is the Albert L. and Madelyne G. Hanson Family Trust Associate Professor in the USC Leonard Davis School of Gerontology with joint appointments as associate professor of biological sciences in the USC College of Letters, Arts and Sciences, and in the Norris Cancer Center.

FOR CLINICIANS AND PATIENTS

Fasting before chemotherapy has unknown risks and benefits for humans, Longo cautioned. Only clinical trials can establish the effectiveness and safety of fasting before chemotherapy.

“Don’t try and do this at home. We need to do the studies,” said Quinn, the USC Norris oncologist.

Source: http://blackwell-synergy.com/doi/abs/10.1111/…

Jérôme Villeneuve; Hugo Galarneau; Marie-Josée Beaudet; Pierrot Tremblay; Ariel Chernomoretz*; Luc Vallières

Department of Oncology and Molecular Endocrinology, Laval University Hospital Research Center, Québec City, Québec, Canada.

* Current address: Departamento de Fisica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 1 Ciudad Universitaria, 1428, Buenos Aires, Argentina

All patients with glioblastoma, the most aggressive and common form of brain cancer, develop cerebral edema. This complication is routinely treated with dexamethasone, a steroidal anti-inflammatory drug whose effects on brain tumors are not fully understood.

Here we show that dexamethasone can reduce glioma growth in mice, even though it depletes infiltrating T cells with potential antitumor activity. More precisely, T cells with helper or cytotoxic function were sensitive to dexamethasone, but not those that were negative for the CD4 and CD8 molecules, including gammadelta and natural killer (NK) T cells.

The antineoplastic effect of dexamethasone was indirect, as it did not meaningfully affect the growth and gene expression profile of glioma cells in vitro. In contrast, hundreds of dexamethasone-modulated genes, notably angiopoietin 2 (Angpt2), were identified in cultured cerebral endothelial cells by microarray analysis.

The ability of dexamethasone to attenuate Angpt2 expression was confirmed in vitro and in vivo. Selective neutralization of Angpt2 using a peptide-Fc fusion protein reduced glioma growth and vascular enlargement to a greater extent than dexamethasone, without affecting T cell infiltration.

In conclusion, this study suggests a mechanism by which dexamethasone can slow glioma growth, providing a new therapeutic target for malignant brain tumors.

Source: http://technologyreview.com/Biotech/20462/
MRI scans could be used to determine which drug will work best against a brain tumor.

By Katherine Bourzac

When patients are diagnosed with glioblastoma, the most common form of brain cancer, they often have only months to live. Even though researchers’ knowledge about this tumor’s biology and genomics has expanded in recent years, no significant treatment strategies have been developed during the past 25 years. Now there is preliminary but strong evidence that the appearance of these tumors in magnetic resonance images (MRIs) can be used to predict their genomic profiles. Researchers hope that MRI will soon be used for dividing glioblastomas into genomic subtypes, in turn allowing doctors to put patients on the best drug before a biopsy is even taken.

At the genetic level, two patients with glioblastoma (or any particular cancer type) may have very different tumors. For example, one patient might respond well to a therapy targeting tumor blood-vessel growth, while the other patient’s tumor might have activated a genetic program that allows it to resist such a therapy. Right now, it’s difficult for doctors to tell these patients apart and to predict responses to many other targeted therapies, so all glioblastoma patients are given the same treatments. Pathologists can perform gene-expression studies on biopsies, but these tests are expensive and not in wide use; MRI scans are standard.

“By tying imaging features to specific biology, we hope to give insights into treatment targets and patient prognosis,” says Michael Kuo, a radiologist at the University of California, San Diego, who led the study connecting MRI scans with glioblastoma genetics. In work described in today’s issue of the Proceedings of the National Academy of Sciences, Kuo’s group identified five visually discernable kinds of tumors strongly associated with particular gene-expression profiles that are tied to targeted therapies. The paper also describes for the first time a particularly aggressive subtype of the disease.

According to the paper, Kuo and his collaborators defined a set of traits present in MRI scans of 22 glioblastoma tumors. “Normally, when a radiologist looks at a tumor, he’s focused on diagnosis: is this a primary tumor, a metastasis, or an infection?” explains Kuo. The San Diego researchers defined a longer list of characteristics, including morphology and the interaction of the tumors with the surrounding tissues. “The premise here is, there is a lot more information in the images than is currently accounted for,” says Kuo.

Then the researchers looked for connections between the ten types of tumors shown in the MRIs and the activity of seven genetic programs by studying the patients’ biopsies using microarrays. These genetic programs included groups of genes associated with blood-vessel growth, cell proliferation, and other characteristic aspects of cancer biology, all of which are targeted by existing drugs. The team also looked for associations between tumor appearance and overexpression of one gene in particular, coding for epidermal growth factor receptor, a cell receptor that’s overactive in many glioblastomas.

Radiologists have seen some of these connections anecdotally but haven’t had the data to back them up, says Patrick Wen, a neuro-oncologist at the Dana-Farber Cancer Institute, in Boston. For example, Wen says, oncologists have suspected the connection between tumor appearance and response to therapies targeting tumor blood vessels demonstrated in Kuo’s study. If further data back up this result, it is one of many that would prove therapeutically useful. Wen says that the results are a very important first step “towards using imaging to tailor treatment without having to take tissue.”

“Gene-expression patterns result in anatomical changes you can see in these images,” says Webster Cavanee, director of the Ludwig Institute for Cancer Research at the University of California, San Diego. Cavanee, who was not involved in Kuo’s research, believes that the connection between imaging and genetics will hold in other cancers, and perhaps other diseases. Last year, Kuo published a paper connecting characteristics of liver tumors in CT scans with gene-expression patterns. This suggests that the connection between anatomical changes and gene expression will hold up across imaging and tumor types alike.

Cavanee and Wen agree that if Kuo’s work holds up in larger studies, it could have a major clinical impact. “An imaging protocol could be powerful,” says Cavanee, because medical imaging is already part of standard cancer care. “The images are already there. It’s a matter of layering information on something that already exists without adding cost–you’re just adding precision.”

Another advantage of using images for molecular profiling rather than biopsies and microarrays is the global view that this affords. “In general, a biopsy does represent the whole tumor,” says Kuo. But some tumors, particularly glioblastomas, may be heterogeneous–part of a tumor might be more vulnerable or resistant to particular drugs than others–and a biopsy only gives information about one region. Microarrays do give much more specific information, but this level of detail might not be needed: MRI scans might be good enough to rapidly get patients on a drug that’s likely to work. And to get a biopsy, “you need to go in physically and get tissue,” which carries risks, says Kuo.

Kuo’s group also identified a particularly malignant version of glioblastoma and connected its MRI scans and genetic profile with poor patient outcomes. “Instead of saying all patients with [glioblastoma] tumors are the same, we can sort them into two subtypes based on outcome,” says Kuo. His work suggests that these patients should be identified and treated more aggressively, while patients with less malignant cancers can be spared the side effects of aggressive treatment.

Wen describes Kuo’s work as an important first step, but a small one. Kuo’s team is currently working to validate its results in a larger group of glioblastoma patients. “Our data suggest we’re going in the right direction,” he says.

More information:

• Non-Invasive Imaging Provides Window Into Genetic Properties of Brain Tumors
• PNAS: Identification of noninvasive imaging surrogates for brain tumor gene-expression modules

Source: http://nytimes.com/2008/03/18/health/18seco.html
Video: Revisiting Melanie McDaniel

March 18, 2008
Second Opinion
By DENISE GRADY

In the pages of a medical journal, Melanie Joy McDaniel is a study subject, listed by her patient number and tumor type. In real life she’s a little girl whose story is a reminder that medical research can change lives and that the pioneers include patients, some of whom are babies.

Melanie was 9 months old when her parents faced an agonizing decision. She had already had two operations for a malignant brain tumor, and doctors could not be sure they had removed all the cancer. She needed more treatment, but standard chemotherapy offered little hope in exchange for its harsh side effects. And yet the McDaniels knew that if they did nothing, the odds were high that the tumor would come back.

Doctors at the Dana-Farber Cancer Institute in Boston offered another option, an experimental treatment. To qualify, a child had to have a progressive cancer, and it had to be terminal. The McDaniels took a gamble and a leap of faith, and signed Melanie up.

“It won’t save her, but it may help other people,” her father, Paul McDaniel, told me in an interview for a Science Times article published in April 2002. Then he paused and added, “Maybe it will save her.”

By then, Melanie had been receiving the test therapy for five months, and her brain tumor, a type called an ependymoma, had not grown. That was encouraging, but the treatment still seemed like a long shot.

After the article was published, I was afraid to call the McDaniels again. I didn’t think Melanie would survive.

Recently, Mr. McDaniel sent me an e-mail message. “Melanie is now 7 years old, attending first grade, and doing very well,” he wrote. “The doctors told us last year that they do not see any residual tumor in her brain. Their original diagnosis was that her tumor had no known cure.”

What had prompted him to get in touch was the death on Jan. 14 of Dr. Judah Folkman, a researcher at Children’s Hospital Boston whose work had led to Melanie’s treatment. Mr. McDaniel wrote that he wanted “to celebrate the accomplishments of Dr. Folkman, who faced resistance on his ideas that, by the grace of God, cured my daughter of an incurable brain tumor.”

Dr. Folkman founded a branch of research based on the theory that tumors need a blood supply in order to grow and can stimulate the formation of new blood vessels — angiogenesis — to feed themselves. If angiogenesis could be stopped, he reasoned, it might be possible to starve tumors. His work ultimately led to useful treatments but took years to gain acceptance in a field that was focused on attacking cancer cells directly.

Melanie McDaniel became one of 20 children with advanced cancer who were enrolled in a study that used drugs strictly to fight angiogenesis. The drugs included two standard anticancer medicines, but in small doses meant to stop blood vessels from forming, not the much bigger amounts needed to poison tumor cells.

The children also took two other drugs that had been found to block angiogenesis. One was Celebrex, usually given for pain and inflammation. The other was thalidomide, notorious for causing stunted limbs and other birth defects when pregnant women took it in the 1960s — damage, it was later learned, that the drug inflicted by halting the growth of blood vessels in the fetus.

Melanie and the other children were given small doses of medicine by mouth every day, instead of big doses intravenously every few weeks. The idea was that continuous treatment might keep blood vessel growth in check, whereas the usual schedule of therapy every few weeks could give new vessels a chance to sprout between doses. Doctors also hoped that the small doses would minimize side effects. The approach is called metronomic, low-dose or antiangiogenic chemotherapy.

“Our goal was to see whether we could keep the kids alive for an additional six months,” said Dr. Mark W. Kieran, Dana-Farber’s director of pediatric medical neuro-oncology.

The study was meant to test the feasibility of using the drugs for 26 weeks. But by the 26th week, seven children were doing so well that their parents refused to give up the drugs.

“Remember, you got onto this trial because your child had a progressive, incurable tumor,” Dr. Kieran said. “Many families said, ‘Why would we stop?’ ”

The McDaniels kept Melanie on the drugs for a year and a half. Then, she was monitored closely with M.R.I. scans.

Finally, last year, her doctors said there were no traces of the tumor left.

Mr. McDaniel said, “She goes to the survivor clinic now, instead of the pediatric brain tumor clinic.”

But the researchers are not claiming credit for Melanie’s recovery. The study was designed primarily to test the drugs’ safety, and it was not large enough to measure their effectiveness.

Dr. Christopher D. Turner, director of pediatric neuro-oncology outcomes research at Dana-Farber, said the surgery might be responsible, but he added: “Her type of tumor almost always comes back. Historically, we know that surgery alone is not usually enough.”

Every doctor encounters “miracle patients” who improve against all odds, Dr. Kieran said. But he also said, “We have a bunch of long-term survivors.”

A report on the study published in 2005 showed that seven children, including Melanie, were still alive a year and half to three years after starting the treatment.

“It’s immensely gratifying,” Dr. Turner said. “The study we did took the drugs we knew are commercially available and combined them in a way that hadn’t been used before. A number of doctors across the country have followed the published paper we did, the regimen, on their own patients, and have given us feedback that they have had some remarkable stories themselves across the country. We have to be careful — it’s not science; it’s anecdote. When someone calls and says, ‘We had a great response,’ what I don’t hear is how many others used it and didn’t have a good response.”

The next step is a larger study. One is already under way, involving 160 children at 12 medical centers, with eight categories of cancer.

“We certainly hope to have some answers within the next couple of years,” Dr. Turner said.

Meanwhile, Melanie, who has an older brother and a younger one and a lot of friends, is a normal little girl whom her mother describes simply as “hilarious.” But her parents know that her type of tumor can always recur, even after many years.

“As much as we’re excited about how good she’s doing, there’s that much fear of it coming back,” said her mother, Amy McDaniel. “It’s always in your mind.

“We need the science to keep going. We need to be armed and ready if it does return.”

Source: http://stjude.org/stjude/v/index.jsp…

Memphis, Tennessee, March 14, 2008

A discovery by St. Jude Children’s Research Hospital scientists suggests a safer way to treat medulloblastoma, a rare but often fatal childhood brain tumor. The group found that one of the brain’s signaling pathways inhibits the growth of the highly aggressive cancer cells.

The researchers discovered that three proteins, designated BMP2, BMP4 and BMP7, halted the growth of medulloblastoma tumors and induced the malignant cells to develop into normal neurons.

“We think we have identified a pathway that can be used to prevent tumor formation and a potential target for therapy,” said Martine F. Roussel, Ph.D., a member of the St. Jude Department of Genetics and Tumor Cell Biology. A report on this work appears in the March 15 issue of “Genes & Development.” Roussel is the paper’s senior author.

Medulloblastoma occurs in the cerebellum, which is located in the lower, rear part of the brain. This cancer strikes about 350 young children in the United States annually. Although treated patients have an overall five-year survival rate of 70 percent, conventional therapies combining surgery, irradiation and chemotherapy frequently lead to permanent neurocognitive impairment.

Several research teams are seeking to decipher the intricate signaling mechanisms that govern the proliferation of cells called granule neuron progenitors (GNPs). These cells go on to develop into neurons in the cerebellum during the first year of life. But the disruption of this differentiation process can trigger medulloblastoma.

“We were interested in whether there were signals that inhibited tumor formation,” Roussel said. “And if there were, which ones were they? Could they be used to identify new therapeutic targets?”

Previous research had shown that spurring GNPs to differentiate into neurons requires that BMPs bind to a set of receptors on the cell surface. This binding results in blocking the activity of a signaling pathway triggered by another molecule called Sonic hedgehog.

“What was not known, and what we now find, is that the effect of BMPs on normal GNP cells is almost exactly mimicked in GNP-like tumor cells,” Roussel said.

In cell culture experiments, her group found that BMPs rapidly cause the degradation of a protein called Math1, which occurs in dividing GNPs, but not in non-proliferating neurons. Twelve hours after BMP treatment, researchers could detect no Math1 and cell growth soon stopped.

The exact way Math1 works remains unknown. However, in mice the protein is vital to the formation of a normal brain. Mice genetically altered so they did not carry the gene for Math1 failed to develop cerebellums.

The St. Jude team also performed gene transfer experiments in mice to test BMPs as a possible medulloblastoma treatment. Using a genetically altered virus, scientists inserted the BMP gene into the cancer cells and showed that the transfer not only halted tumor growth, but induced the cancer cells to change into neurons.

BMPs, however, are extremely expensive to purify. Currently, the St. Jude researchers are searching for tiny, less expensive biological molecules that might mimic the action of BMPs in medulloblastoma.

Roussel also suggests that the ability of BMPs to transform medulloblastoma cells into normal neurons, coupled with a discovery made earlier at St. Jude, could offer a combination treatment for the cancer. In 2004, a St. Jude team reported that an experimental drug called HhAntag, which inhibits Sonic hedgehog signaling, led to the deaths of medulloblastoma cells and the elimination of these tumors in treated mice. However, the team also found that treatment with HhAntag interfered with bone development in the animals, suggesting an unwelcome side effect in young children.

Roussel’s group reported that although both the Sonic hedgehog and BMP pathways play roles in regulating cell division, they do so in distinctly different ways. This led to testing the two in combination. “What we a found is that using a lower dose of the Sonic hedgehog inhibitor in combination with BMP gives the same therapeutic effect as high doses of the hedgehog inhibitor,” Roussel said. “We hope that by reducing the levels of both compounds, we might prevent the secondary effects on bone of this potential therapy.”

Other authors of this study include Haotian Zhao, Olivier Ayrault and Frederique Zindy (St. Jude) and Jee-Hae Kim (Rockefeller University, New York).

This work was supported by the National Institutes of Health, a Cancer Core Grant, La Fondation pour la Recherche Medicale, the Gephardt Endowed Fellowship Signal Transduction and ALSAC.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.

URL: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=298507

TUSTIN, Calif., March 11, 2008
PRNewswire-FirstCall via COMTEX News Network

Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus infection, today released an update from two clinical trials assessing its targeted therapy Cotara(R) in the treatment of glioblastoma multiforme (GBM), the most deadly form of brain cancer. The Cotara clinical update covers the first cohort of patients in its dosimetry trial as well as experience to date in an ongoing Phase II safety and efficacy trial. In patients treated in the studies, Cotara appears to be safe and well tolerated, with no dose-limiting adverse events. Patients who are continuing in the trials are being monitored for safety and overall survival, with several surpassing the median expected survival time for relapsed GBM patients. The recent addition of new clinical sites in both the dosimetry and Phase II trials is expected to help accelerate the pace of patient enrollment going forward. The company also announced that data from the first patient cohort in the dosimetry trial has been accepted for presentation at the 2008 ASCO Annual Meeting.

“We are encouraged by early results from these two Cotara clinical studies and look forward to presenting data from the dosimetry trial at the upcoming ASCO Annual Meeting,” said Steven W. King, president and CEO of Peregrine. “In view of the short expected survival time of approximately six months in this patient population, it is promising that we have early GBM patients in these trials who have survived past the six-month timeframe, with one patient now surviving 15 months post-treatment.”

The open-label Phase I dosing and dosimetry study at U.S. brain cancer centers is enrolling GBM patients with recurrent disease. Patients in this trial receive an initial imaging dose of Cotara before receiving the therapeutic dose. The study’s main objectives are to confirm the maximum tolerated dose, to determine radiation dosimetry and to assess overall patient survival, progression-free survival and the proportion of patients alive at six months following Cotara administration. In the three GBM patients enrolled in the first cohort, Cotara was safe and well tolerated, with no dose-limiting toxicities. Patients have been followed post-treatment to determine overall survival, with the first treated patient currently surviving 15 months post-treatment and the last treated patient currently surviving four months post-treatment. Dosimetry analysis indicates that Cotara was concentrated only in the tumor in these patients, and not in other organs.

Mr. King added, “With enrollment of the second patient cohort underway, we welcome Dr. William Shapiro of the Barrow Neurological Institute as principal investigator of our newest dosimetry study clinical site. Dr. Shapiro successfully participated in earlier Cotara studies and we are delighted that his center is now participating in the Cotara dosimetry trial.”

“We are pleased to join the dosing and dosimetry trial of Cotara for the treatment of recurrent GBM,” said Dr. William Shapiro, director, neuro oncology program; Marley chair, neurology; professor of neurology, University of Arizona College of Medicine; and Cotara principal investigator at the Barrow Neurological Institute. “GBM is a deadly disease with very poor survival prospects for relapsed patients, and improved therapies are urgently needed. We are hopeful that the encouraging survival trends seen in previous Cotara studies will be replicated in larger trials going forward, and we view this dosimetry trial as an important step on that path.”

Mr. King continued, “We are also pleased to report that we have recently added additional clinical sites to the Cotara Phase II study, increasing the total participating centers from three sites to eight sites. We anticipate enhanced enrollment rates going forward, particularly in view of the quality and enthusiasm of the investigators we have recruited. We look forward to reporting further interim results from the Cotara program as we achieve additional enrollment milestones in the coming months.”

The objectives of the open-label Phase II trial are to confirm the safety of the selected dose of Cotara and to obtain estimates of overall patient survival, progression-free survival and the proportion of patients alive at six months in GBM patients at first relapse. Patients in the trial are receiving a single infusion of Cotara by convection-enhanced delivery (CED), a technique that delivers the agent to the tumor with great precision. Patients receive brain scans at eight-week intervals post-treatment. Total enrollment in the 40-patient trial has reached the 20% completion mark. Patients who are continuing in the trials are being monitored for safety and overall survival, with the first dosed patient having reached eight months of survival post-treatment. Patient screening for the trial will continue until all 40 patients have been enrolled.

About Cotara(R)

Cotara is an experimental treatment for brain cancer that links a radioactive isotope to a targeted monoclonal antibody. This monoclonal antibody is designed to bind to a type of DNA that is exposed only on dead and dying cells. Solid tumors have many dead and dying cells at their center. Cotara’s targeting mechanism enables it to home in on these cells, delivering its radioactive “payload” directly to the center of the tumor mass and thereby destroying it “from the inside out” with minimal radiation exposure to healthy tissue. Cotara is delivered using convection-enhanced delivery (CED), which targets the specific tumor site in the brain. In a previous clinical study, a subset of patients with recurrent glioblastoma treated with Cotara achieved a median survival of 38 weeks, a 58% increase over the median survival time of 24 weeks for patients treated with standard of care therapy. In this study, 25% of 28 recurrent patients survived for more than a year post-treatment and 10% of patients survived for more than three years. These data are considered a promising development in this deadly disease. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative product candidates in clinical trials for the treatment of cancer and hepatitis C virus (HCV) infection. The company is pursuing three separate clinical programs in cancer and HCV infection with its lead product candidates bavituximab and Cotara(R). Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. (http://www.avidbio.com), which provides development and bio-manufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://peregrineinc.com.

More information:

• Iodine I 131 Monoclonal Antibody TNT-1/B in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme
• Safety and Radiation Distribution Study of Iodine 131I-chTNT-1/B Monoclonal Antibody (Cotara®) in Patients With Recurrent Glioblastoma Multiforme

Animal study raises caution on using signal transduction inhibitors in children

Source: http://eurekalert.org/pub_releases/…

A novel drug that fully eliminated brain tumors from mice in a dramatic 2004 study has shown a darker side—causing permanent bone damage in younger mice. The researcher who conducted both studies says the disappointing new finding raises concerns about using similar drugs to treat children’s cancers, at least until there is a more thorough understanding of possible risks.

Tom Curran, Ph.D., a developmental biologist at The Children’s Hospital of Philadelphia, led the study, published in the March 2008 issue of the journal Cancer Cell. The drug in question, HhAntag, is a signal transduction inhibitor–an agent that blocks signals along a biological pathway. In mice specially bred for these studies by Curran’s research group, HhAntag specifically acts against signals on a pathway leading to medulloblastoma, a type of brain tumor found mostly in children.

Much current cancer research has focused on signal transduction inhibitors (STIs) because of their potential to interrupt specific biological pathways that give rise to cancer. To date, only one STI has been approved by the Food and Drug Administration for use in children. That drug, which acts on different biological pathways than HhAntag does, has not been associated with any developmental defects in children. However, other STIs are currently in pediatric clinical trials.

His team’s new findings, says Curran, raise a strong caution. “While it is not clear that the bone defects we observed in mice would also occur in children, and while signal transduction inhibitors may still represent a highly promising approach to treating pediatric cancer, it may be important to perform preclinical testing in young animals before moving ahead to clinical trials,” he added. Young animals could provide a model of a drug’s potential effects during childhood development.

The drug used by Curran’s group acts on the hedgehog (Hh) pathway, which is known to play multiple roles during the development of mammals. Mutations of genes along that pathway lead to different cancers, including medulloblastoma, the most common cancerous brain tumor in children. Because conventional treatment with surgery, radiation and chemotherapy causes serious long-term side effects such as ataxia (a movement disorder) and cognitive impairments, the researchers sought novel, less toxic treatments for medulloblastoma.

In 2001, using genetic engineering, Curran bred mice to develop medulloblastoma. He then treated those mice with HhAntag, which had previously been developed by a biotech company for treating skin cancer in adults. In 2004, while at St. Jude’s Children’s Research Hospital, Curran reported highly promising results from the mouse studies. At high doses, the drug caused the tumors to shrink and in some cases, disappear entirely. The treated mice also survived much longer than untreated mice, with no serious side effects.

The drug seemed to be an unusually strong candidate for trials in children with the type of medulloblastoma having gene mutations on the Hh pathway—about a third of cases.

However, when Curran’s group tested the agent on young mice (10 to 14 days old, in contrast to the adult mice tested previously), they found an unpleasant surprise: serious impairments to developing bones. The mice were smaller, with lower weight and shorter bones than untreated mice, and the effects were not reversible. Even four doses of the drug permanently stunted their growth. “We already knew that the same biological pathway involved in the growth of tumors was also involved in bone development,” said Curran, “but we did not expect temporary inhibition to cause an irreversible change in bone growth.”

While the current studies were disappointing, said Curran, they do not totally rule out a future role for HhAntag as a treatment for medulloblastoma. “The effects we see in mice may be less dramatic in children, and there may be methods of delivering this drug directly to brain tissue, while avoiding bones. Alternatively, we might discover other drugs that act on the hedgehog pathway but selectively target brain tissue.” Another approach, he adds, may be to use HhAntag only in older children who have already completed their growth, or in the admittedly small proportion of medulloblastoma patients who are adults.

“Signal transduction inhibitors such as this drug may still prove beneficial in treating children’s cancers, but our findings raise questions about possible adverse effects during childhood development,” said Curran.

###

The National Institutes of Health supported the study. The biotech company Genentech provided supplies of the drug used in the research. Curran’s co-authors were Hiromichi Kimura, formerly of St. Jude’s Children’s Research Hospital; and Jessica M.Y. Ng, of The Children’s Hospital of Philadelphia.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://chop.edu.

Contact: John Ascenzi | 267.426.6055 |

More Information:

• Transient Inhibition of the Hedgehog Pathway in Young Mice Causes Permanent Defects in Bone Structure

URL: http://wired.com/print/science/discoveries/news/2008/03/mri_vision

By Brandon Keim 03.05.08 | 6:40 PM

Scientists have developed a computer model that predicts the brain patterns elicited by looking at different images — a possible first step on the path to mind reading.
Image: University of California at Berkeley

Tell me what you see.

On second thought, don’t: A computer will soon be able to do it, simply by analyzing the activity of your brain.

That’s the promise of a decoding system unveiled this week in Nature by neuroscientists from the University of California at Berkeley.

The scientists used a functional magnetic resonance imaging machine — a real-time brain scanner — to record the mental activity of a person looking at thousands of random pictures: people, animals, landscapes, objects, the stuff of everyday visual life. With those recordings the researchers built a computational model for predicting the mental patterns elicited by looking at any other photograph. When tested with neurological readouts generated by a different set of pictures, the decoder passed with flying colors, identifying the images seen with unprecedented accuracy.

“No one that I know would ever have guessed our decoder would do this well,” study co-author Jack Gallant said.

As the decoder is refined, it could be used to explore the phenomenon of visual attention — concentration on one part of a complicated scene — and then to illuminate the dimly understood intricacies of the mind’s eyes.

“One day it may even be possible to reconstruct the visual content of dreams,” Gallant said.

After that, the decoding model could be harnessed for more visionary purposes: early warning systems for neurological diseases or interfaces that allow paralyzed people to engage with the world.

Other uses may not be so noble, such as marketing campaigns crafted for maximum mental penetration or invasions of mental privacy mounted in the name of fighting terrorism and crime.

Those technologies remain decades away, but researchers say it’s not too soon to think about them, especially if research progresses at the pace set by this study.

Earlier decoders could only tell whether someone looked at a general type of image — at a dog, for example — but couldn’t identify more specific photos, such as a small dog eating a bone. They’ve also been incapable of predicting what thought patterns an image would provoke.

The Berkeley model overcame both those limitations.

“It’s quite tedious to measure every possible thought you might encounter, then measure the brain activity for that,” said John-Dylan Haynes, a Max Planck Institute neuroscientist who was not involved in the study. “This is a big step forward.”

Future steps involve expanding the decoder beyond its current focus on the brain’s primary visual cortex, which represents general forms but doesn’t handle the more complicated optical information processed in other parts of the brain.

More detail is also required, as the brain scanners used for the study measure blood flow caused by neural activity at a relatively coarse resolution of two cubic millimeters.

A higher-resolution, fully reconstructive decoder could help researchers chart the incredibly complex processes underlying visual perception. Gallant also hopes it could be used to detect early symptoms of neurological diseases like Alzheimer’s and Parkinson’s.

Eventually, Haynes said, the Berkeley model could be harnessed for something akin to mind reading.

“We want not only to decode people’s perceptions, but also high-level mental states: people’s intentions, their plans,” Haynes said.

But Gallant warned of technological malfeasance. In the courtroom, mental readouts could have the same problems as eyewitness testimony, which is often unreliable and biased even though witnesses believe they’re telling the truth.

The allure of reading minds to prove innocence or guilt, Haynes said, could override concerns about mental privacy — an ethically ambiguous conflict. More obviously dubious is the possible use of mind-reading machines by marketers.

“There’s some things we can do, and some we can’t,” Haynes said. “Some things are very easy, and others are not. But it’s vital to think about the ethics now.”

More Information:

• Mind-reading with a brain scan

Jessica Marszalek | March 5, 2008 - 3:37PM
URL: http://brisbanetimes.com.au/news/queensland/…

Scientists at a new cancer research facility will use a unique method to identify specific cells that grow brain tumours as they seek a cure for the deadly disease.

The Australian Cancer Research Foundation Brain Tumour Research Centre was formally opened today at the University of Queensland’s Queensland Brain Institute (QBI).

QBI director Professor Perry Bartlett said the centre operated a world-first automated screening facility designed for testing and identifying stem cells which caused tumours to grow.

He said the machine was traditionally used to sort blood cells but had been converted to sort solid cells.

Prof Bartlett said 10 years of research by the QBI had identified a cell in the brain that produced new nerve cells but could also “go haywire and produce tumours”.

“In specific terms, this new facility allows us to take a brain tumour out of a patient, dissociate it into single cells and examine every one of those cells for the rogue cell that’s causing the tumour,” he said.

“Up until now, the reason brain tumours have been hard to treat is that we could never identify the rogue cell amongst all these other cells that exist there.”

Identified cells would then be transplanted into animals to see which cells caused malignancy and test which drugs worked in treatment.

Prof Bartlett said treatment could require several different drugs, and be tailored to individual patients.

State Health Minister Stephen Robertson, who opened the centre today, said the research was vital considering an 21 per cent increase in the past 10 years of malignant brain tumours.

“The average life expectancy of patients with aggressive forms of brain cancer is often less than a year, so groundbreaking research is all the more pertinent,” Mr Robertson said.

The centre will employ 250 staff and will also be available for use by clinicians working in Queensland Health facilities.

More information:

• World-first stem cell screening facility to target brain tumours