Molecular biologists devise strategy to starve brain tumors

Thursday 3 October 2013

Islamabad, Oct 4 (Newswire): Brain tumor researchers have found that brain tumors arise from cancer stem cells living within tiny protective areas formed by blood vessels in the brain. Killing those cells is a promising strategy to eliminate tumors and prevents them from re-growing.

The researchers have found that drugs that block new blood vessel formation can destroy the protected areas and stop cancer from developing.

Brain tumors are often deadly. Figuring out a way to wipe them out has been a mystery for scientists. But now, a new discovery may offer clues and hope for those with even the most hard-to-treat tumors.

In the last two months, Will Pappas has had three surgeries, chemo and radiation.

"You hold out hope that well, it's just something little, and they can get it all. And then it wasn't. Then you think, well, at least it's not cancerous, and then it is," Cayce Pappas, Will's mom, says.

"It" is a brain tumor -- the stubborn kind that's hard to treat. In fact, doctors gave this seven-year-old only a 20 percent chance of surviving. Stories like Will's have molecular biologists determined to find a way to destroy brain tumors.

"It's what makes us all come to work in the morning," Richard Gilbertson, a molecular biologist from St. Jude Children's Hospital, says.

For years, researchers thought all cells inside a tumor were the same. But recently, they've discovered something different -- a small group of cancer stem cells.

"They give rise to all the cells that make up the cancer," Dr. Gilbertson explains.

Dr. Gilbertson's research shows those cancer stem cells live close to blood vessels, which fuel them. In lab experiments, he's proven drugs that target the blood vessels also destroy the cancer stem cells and can ultimately wipe out the tumor.

"So, if you can target those cells, you can have a devastating effect on the disease," Dr. Gilbertson says. Drugs like Avastin and Tarceva are now being tested in humans to see if they can target the cancer stem cells. "It's this tangible way of actually getting at the heart of the disease," Dr. Gilbertson says.

Will is taking the drug Tarceva. His mom is hoping it will work a miracle.

"That would be amazing. We would jump at the opportunity to increase our odds. He's still got a lot left to do," Cayce says.

Dr. Gilbertson says other cancers, like those of the blood, breast and colon, also contain cancer stem cells and may be treated in a similar way in the future.

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DNA of 50 breast cancer patients decoded

Islamabad, Oct 4 (Newswire): In the single largest cancer genomics investigation reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells.

This comparison allowed researchers to find mutations that only occurred in the cancer cells.

They uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The work was presented at the American Association for Cancer Research 102nd Annual Meeting 2011.

In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, says Matthew J. Ellis, MD, PhD, professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project.

"Cancer genomes are extraordinarily complicated," Ellis says. "This explains our difficulty in predicting outcomes and finding new treatments."

To undertake the massive task, Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine collaborated with the university's Genome Institute to sequence more than 10 trillion chemical bases of DNA -- repeating the sequencing of each patient's tumor and healthy DNA about 30 times to ensure accurate data.

"The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," Ellis says.

The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients in the trial had what is called estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumors grow.

To slow tumor growth and make the tumors easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work. Twenty-four of the 50 tumor samples came from patients whose tumors were resistant to this treatment, and 26 came from patients whose tumors responded. Comparing the two groups might help explain why some estrogen-receptor-positive breast cancer patients do well with estrogen-lowering drugs and others poorly.

Confirming previous work, Ellis and colleagues found that two mutations were relatively common in many of the patients' cancers. One called PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen. Another called TP53 is present in about 20 percent.

Adding to this short list of common mutations, Ellis and colleagues found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of estrogen-receptor-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.

"To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock," Ellis says.

In addition, they found 21 genes that were also significantly mutated, but at much lower rates -- never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stresses their importance.

"Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women," he says.

Ellis points out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them.

"You may find the rare breast cancer patient whose tumor has a mutation that's more commonly found in leukemia, for example. So you might give that breast cancer patient a leukemia drug," Ellis says.

But such treatment is only possible when the cancer's genetics are known in advance. Ideally, Ellis says, the goal is to design treatments by sequencing the tumor genome when the cancer is first diagnosed.

"We get good therapeutic ideas from the genomic information," he says. "The near-term goal is to use information on whole genome sequencing to guide a personalized approach to the patient's treatment."

This work builds on previous collaborations between Washington University oncologists and the Genome Institute. In a study published in Nature, they reported the complete tumor and normal DNA sequences of a woman with "triple-negative" breast cancer, a particularly aggressive type that is difficult to treat and more common in younger women and African-Americans.

While many mutations are rare or even unique to one patient, Ellis says quite a few can be classified on the basis of common biological effects and therefore could be considered together for a particular therapeutic approach.

Ellis looks to future work to help make sense of breast cancer's complexity. But these highly detailed genome maps are an important first step.

"At least we're reaching the limits of the complexity of the problem," he says. "It's not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome."

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Catching cancer with carbon nanotubes: New device to test blood can spot cancer cells, HIV on the fly

Islamabad, Oct 4 (Newswire): A Harvard bioengineer and an MIT aeronautical engineer have created a new device that can detect single cancer cells in a blood sample, potentially allowing doctors to quickly determine whether cancer has spread from its original site.

The microfluidic device, described in the March 17 online edition of the journal Small, is about the size of a dime, and could also detect viruses such as HIV.

It could eventually be developed into low-cost tests for doctors to use in developing countries where expensive diagnostic equipment is hard to come by, says Mehmet Toner, professor of biomedical engineering at Harvard Medical School and a member of the Harvard-MIT Division of Health Sciences and Technology.

Toner built an earlier version of the device four years ago. In that original version, blood taken from a patient flows past tens of thousands of tiny silicon posts coated with antibodies that stick to tumor cells. Any cancer cells that touch the posts become trapped. However, some cells might never encounter the posts at all.

Toner thought if the posts were porous instead of solid, cells could flow right through them, making it more likely they would stick. To achieve that, he enlisted the help of Brian Wardle, an MIT associate professor of aeronautics and astronautics, and an expert in designing nano-engineered advanced composite materials to make stronger aircraft parts.

Out of that collaboration came the new microfluidic device, studded with carbon nanotubes, that collects cancer cells eight times better than the original version.

Captured by nanotubes

Circulating tumor cells (cancer cells that have broken free from the original tumor) are normally very hard to detect, because there are so few of them -- usually only several cells per 1-milliliter sample of blood, which can contain tens of billions of normal blood cells. However, detecting these breakaway cells is an important way to determine whether a cancer has metastasized.

"Of all deaths from cancer, 90 percent are not the result of cancer at the primary site. They're from tumors that spread from the original site," Wardle says.

When designing advanced materials, Wardle often uses carbon nanotubes -- tiny, hollow cylinders whose walls are lattices of carbon atoms. Assemblies of the tubes are highly porous: A forest of carbon nanotubes, which contains 10 billion to 100 billion carbon nanotubes per square centimeter, is less than 1 percent carbon and 99 percent air. This leaves plenty of space for fluid to flow through.

The MIT/Harvard team placed various geometries of carbon nanotube forest into the microfluidic device. As in the original device, the surface of each tube can be decorated with antibodies specific to cancer cells. However, because the fluid can go through the forest geometries as well as around them, there is much greater opportunity for the target cells or particles to get caught.

The researchers can customize the device by attaching different antibodies to the nanotubes' surfaces. Changing the spacing between the nanotube geometric features also allows them to capture different sized objects -- from tumor cells, about a micron in diameter, down to viruses, which are only 40 nm.

The researchers are now beginning to work on tailoring the device for HIV diagnosis. Toner's original cancer-cell-detecting device is now being tested in several hospitals and may be commercially available within the next few years.

Rashid Bashir, director of the Micro and Nanotechnology Laboratory at the University of Illinois at Urbana-Champaign, says that the ability to filter specific particles, cells or viruses from a blood sample so they can be analyzed is a critical step towards creating handheld diagnostic devices.

"Anything you can do to improve capture efficiency, or anything novel you can do to get the particles to interact with a surface more effectively, will help with sample preparation," says Bashir, who was not part of the research team.

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