(Image caption: A cancer cell containing the nanoparticles. The nanoparticles are coloured green, and have entered the nucleus, which is the area in blue. Credit: M Welland)

“Trojan horse” treatment could beat brain tumours

A smart technology which involves smuggling gold nanoparticles into brain cancer cells has proven highly effective in lab-based tests.

A “Trojan horse” treatment for an aggressive form of brain cancer, which involves using tiny nanoparticles of gold to kill tumour cells, has been successfully tested by scientists.

The ground-breaking technique could eventually be used to treat glioblastoma multiforme, which is the most common and aggressive brain tumour in adults, and notoriously difficult to treat. Many sufferers die within a few months of diagnosis, and just six in every 100 patients with the condition are alive after five years.

The research involved engineering nanostructures containing both gold and cisplatin, a conventional chemotherapy drug. These were released into tumour cells that had been taken from glioblastoma patients and grown in the lab.

Once inside, these “nanospheres” were exposed to radiotherapy. This caused the gold to release electrons which damaged the cancer cell’s DNA and its overall structure, thereby enhancing the impact of the chemotherapy drug.

The process was so effective that 20 days later, the cell culture showed no evidence of any revival, suggesting that the tumour cells had been destroyed.

While further work needs to be done before the same technology can be used to treat people with glioblastoma, the results offer a highly promising foundation for future therapies. Importantly, the research was carried out on cell lines derived directly from glioblastoma patients, enabling the team to test the approach on evolving, drug-resistant tumours.

The study was led by Mark Welland, Professor of Nanotechnology at the Department of Engineering and a Fellow of St John’s College, University of Cambridge, and Dr Colin Watts, a clinician scientist and honorary consultant neurosurgeon at the Department of Clinical Neurosciences. Their work is reported in the Royal Society of Chemistry journal, Nanoscale.

“The combined therapy that we have devised appears to be incredibly effective in the live cell culture,” Professor Welland said. “This is not a cure, but it does demonstrate what nanotechnology can achieve in fighting these aggressive cancers. By combining this strategy with cancer cell-targeting materials, we should be able to develop a therapy for glioblastoma and other challenging cancers in the future.”

To date, glioblastoma multiforme (GBM) has proven very resistant to treatments. One reason for this is that the tumour cells invade surrounding, healthy brain tissue, which makes the surgical removal of the tumour virtually impossible.

Used on their own, chemotherapy drugs can cause a dip in the rate at which the tumour spreads. In many cases, however, this is temporary, as the cell population then recovers.

“We need to be able to hit the cancer cells directly with more than one treatment at the same time” Dr Watts said. “This is important because some cancer cells are more resistant to one type of treatment than another. Nanotechnology provides the opportunity to give the cancer cells this ‘double whammy’ and open up new treatment options in the future.”

In an effort to beat tumours more comprehensively, scientists have been researching ways in which gold nanoparticles might be used in treatments for some time. Gold is a benign material which in itself poses no threat to the patient, and the size and shape of the particles can be controlled very accurately.

When exposed to radiotherapy, the particles emit a type of low energy electron, known as Auger electrons, capable of damaging the diseased cell’s DNA and other intracellular molecules. This low energy emission means that they only have an impact at short range, so they do not cause any serious damage to healthy cells that are nearby.

In the new study, the researchers first wrapped gold nanoparticles inside a positively charged polymer, polyethylenimine. This interacted with proteins on the cell surface called proteoglycans which led to the nanoparticles being ingested by the cell.

Once there, it was possible to excite it using standard radiotherapy, which many GBM patients undergo as a matter of course. This released the electrons to attack the cell DNA.

While gold nanospheres, without any accompanying drug, were found to cause significant cell damage, treatment-resistant cell populations did eventually recover several days after the radiotherapy. As a result, the researchers then engineered a second nanostructure which was suffused with cisplatin.

The chemotherapeutic effect of cisplatin combined with the radiosensitizing effect of gold nanoparticles resulted in enhanced synergy enabling a more effective cellular damage. Subsequent tests revealed that the treatment had reduced the visible cell population by a factor of 100 thousand, compared with an untreated cell culture, within the space of just 20 days. No population renewal was detected.

The researchers believe that similar models could eventually be used to treat other types of challenging cancers. First, however, the method itself needs to be turned into an applicable treatment for GBM patients. This process, which will be the focus of much of the group’s forthcoming research, will necessarily involve extensive trials. Further work needs to be done, too, in determining how best to deliver the treatment and in other areas, such as modifying the size and surface chemistry of the nanomedicine so that the body can accommodate it safely.

Sonali Setua, a PhD student who worked on the project, said: “It was hugely satisfying to chase such a challenging goal and to be able to target and destroy these aggressive cancer cells. This finding has enormous potential to be tested in a clinical trial in the near future and developed into a novel treatment to overcome therapeutic resistance of glioblastoma.”

Welland added that the significance of the group’s results to date was partly due to the direct collaboration between nanoscientists and clinicians. “It made a huge difference, as by working with surgeons we were able to ensure that the nanoscience was clinically relevant,” he said. “That optimises our chances of taking this beyond the lab stage, and actually having a clinical impact.”

Brain tumour cells found circulating in blood

German scientists have discovered rogue brain tumour cells in patient blood samples, challenging the idea that this type of cancer doesn’t generally spread beyond the brain.

Researchers from the University Medical Center Hamburg-Eppendorf, in Hamburg, found that patients with an aggressive form of brain tumour known as glioblastoma multiforme sometimes have tumour cells circulating in their blood.

The discovery could help doctors improve the way they monitor how the disease progresses, and could have implications for treatment.

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To Advance Care for Patients with Brain Metastases: Reject Five Myths

A blue-ribbon team of national experts on brain cancer says that professional pessimism and out-of-date “myths,” rather than current science, are guiding — and compromising — the care of patients with cancers that spread to the brain.

In a special article published in the July issue of Neurosurgery, the team, led by an NYU Langone Medical Center neurosurgeon, argues that many past, key clinical trials were designed with out-of-date assumptions and the tendency of some physicians to “lump together” brain metastases of diverse kinds of cancer, often results in less than optimal care for individual patients. Furthermore, payers question the best care when it deviates from these misconceptions, the authors conclude.

“It’s time to abandon this unjustifiable nihilism and think carefully about more individualized care,” says lead author of the article, Douglas S. Kondziolka, M.D., MSc, FRCSC, Vice Chair of Clinical Research and Director of the Gamma Knife Program in the Department of Neurosurgery at NYU Langone.

The authors — who also say medical insurers help perpetuate the myths by denying coverage that deviates from them — identify five leading misconceptions that often lead to poorer care:

1. All tumor cell types act the same way once they spread to the brain. This oversimplification means that doctors assume that histologically diverse cancers respond the same way to chemotherapy and are equally sensitive (or insensitive) to radiation. It also means that patients are all assumed to be at the same risk of subsequent brain cancer relapses, and development of additional metastatic lesions; and that survival rates are similar as well. The authors point out that this type of thinking overlooks important biological differences in brain metastases resulting from different types of cancer, such as those originating in the lung, breast or skin.
2. The number of brain metastases is the best indicator for guiding management of the disease. Such strict adherence to quantity, the authors say, can wrongly limit treatment options. Physicians should look at total tumor burden, including the size and scope of metastases, rather than just how many metastases occur.
3. All cancers detectable in the brain already reflect the presence of micrometastases, or  smaller, newly formed tumors too miniscule to detect. Evidence, the authors say, suggests otherwise, and aggressively monitoring for, and treating, individual brain metastases can, in fact, improve tumor control and patient survival.
4. Whole brain radiation (WBR) is generally unjustified because it will cause disabling cognitive dysfunction if a patient lives long enough. Dr. Kondziolka and his co-authors say the risks and benefits of WBR should be evaluated for each patient, and that new studies examining the cognitive impact of WBR on thinking and learning are underway.
5. Most brain metastases cause obvious symptoms, making regular screening for them unnecessary, and unlikely to affect survival. The authors counter that advances in screening allow metastases to be detected earlier, and treated sooner, before symptoms occur.

“We are in an era of personalized medicine,” Dr. Kondziolka says, “and we need to begin thinking that way.” The authors further write: “It is time for fresh thinking and new critical analyses,” urging consideration of updated clinical trial designs that include comparison of matched cohorts and cost effectiveness factors. In addition to research that pays more attention to specific cell types and overall tumor burden, investigators should focus on tools available from advances in molecular biology and genetic subtyping and on efforts to learn “why some patients with a given primary cancer develop brain tumors and others do not.”

Ultimately, the authors hope better stratifying patients will improve care for patients with diverse brain metastases.

Longer Telomeres Linked to Risk of Brain Cancer

New genomic research led by UC San Francisco scientists reveals that two common gene variants that lead to longer telomeres, the caps on chromosome ends thought by many scientists to confer health by protecting cells from aging, also significantly increase the risk of developing the deadly brain cancers known as gliomas.

The genetic variants, in two telomere-related genes known as TERT and TERC, are respectively carried by 51 percent and 72 percent of the general population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.

The research was published online in Nature Genetics on June 8, 2014.

“There are clearly high barriers to developing gliomas, perhaps because the brain has special protection,” said Margaret Wrensch, MPH, PhD, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research at UCSF and senior author of the new study. “It’s not uncommon for people diagnosed with glioma to comment, ‘I’ve never been sick in my life.’”

In a possible example of this genetic balancing act between risks and benefits of telomere length, in one dataset employed in the current study—a massive genomic analysis of telomere length in nearly 40,000 individuals conducted at the University of Leicester in the United Kingdom—shorter telomeres were associated with a significantly increased risk of cardiovascular disease.

“Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they’re supposed to, which is one of the hallmarks of cancer,” said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF’s Helen Diller Family Comprehensive Cancer Center.

In the first phase of the new study, researchers at UCSF and The Mayo Clinic College of Medicine analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work confirmed a link between TERT and gliomas that had been made in previous UCSF research, and also identified TERC as a glioma risk factor for the first time.

Since both genes have known roles in regulating the action of telomerase, the enzyme that maintains telomere length, the research team combed the University of Leicester data, and they found that the same TERT and TERC variants associated with glioma risk were also associated with greater telomere length.

UCSF’s Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.

In much research, longer telomeres have been considered a sign of health—for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.

Walsh said the relevance of the new research should extend beyond gliomas, since TERT variants have also been implicated in lung, prostate, testicular and breast cancers, and TERC variants in leukemia, colon cancer and multiple myeloma. Variants in both TERT and TERC have been found to increase risk of idiopathic pulmonary fibrosis, a progressive disease of the lungs.

In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration,” the authors write.

Brain cell find points to new therapies

Insights into how brain cells are produced could lead to treatments for brain cancer and other brain-related disorders.

Scientists have gained new understanding of the role played by a key molecule that controls how and when nerve and brain cells are formed - a process that allows the brain to develop and keeps it healthy.

Their findings could help explain what happens when cell production goes out of control, which is a fundamental characteristic of many diseases including cancer.

Regulatory systems

Researchers have focused on a RNA molecule, known as miR-9, which is linked to the development of brain cells, known as neurons and glial cells.

They have shown that a protein called Lin28a regulates the production of miR-9, which in turn controls the genes involved in brain cell development and function.

Scientists carried out lab studies of embryonic cells, which can develop into neurons, to determine how Lin28a controls the amount of miR-9 that is produced.

Complex pathways

They found that in embryonic cells, Lin28a prevents production of miR-9 by triggering the degradation of its precursor molecule.

In developed brain cells, Lin28a is no longer produced, which enables miR-9 to accumulate and function.

In cancer cells, Lin28a production is re-established, and as a result this natural process is disrupted.

Lab experiments

Researchers used a series of lab tests to unravel the complex processes that are directed by the Lin28a protein.

They say further studies could help explain fully the role of Lin28a and miR-9 in brain development, and pave the way to the development of novel therapies.

The study, published in Nature Communications, was supported by the Wellcome Trust and the Medical Research Council.

Understanding more of the complex science behind the fundamental processes of cell development will helps us learn more about what happens when this goes wrong – and what might be done to prevent it. -Dr Gracjan Michlewski (School of Biological Sciences)

(Image: iStock)

Blocking DNA repair mechanisms could improve radiation therapy for brain cancer

UT Southwestern Medical Center researchers have demonstrated in both cancer cell lines and in mice that blocking critical DNA repair mechanisms could improve the effectiveness of radiation therapy for highly fatal brain tumors called glioblastomas.

Radiation therapy causes double-strand breaks in DNA that must be repaired for tumors to keep growing. Scientists have long theorized that if they could find a way to block repairs from being made, they could prevent tumors from growing or at least slow down the growth, thereby extending patients’ survival. Blocking DNA repair is a particularly attractive strategy for treating glioblastomas, as these tumors are highly resistant to radiation therapy. In a study, UT Southwestern researchers demonstrated that the theory actually works in the context of glioblastomas.

“This work is informative because the findings show that blocking the repair of DNA double-strand breaks could be a viable option for improving radiation therapy of glioblastomas,” said Dr. Sandeep Burma, Associate Professor of Radiation Oncology in the division of Molecular Radiation Biology at UT Southwestern.

His lab works on understanding basic mechanisms by which DNA breaks are repaired, with the translational objective of improving cancer therapy with DNA damaging agents. Recent research from his lab has demonstrated how a cell makes the choice between two major pathways that are used to repair DNA breaks – non-homologous end joining (NHEJ) and homologous recombination (HR). His lab found that enzymes involved in cell division called cyclin-dependent kinases (CDKs) activate HR by phosphorylating a key protein, EXO1. In this manner, the use of HR is coupled to the cell division cycle, and this has important implications for cancer therapeutics. These findings were published April 7 in Nature Communications.

While the above basic study describes how the cell chooses between NHEJ and HR, a translational study from the Burma lab demonstrates how blocking both repair pathways can improve radiotherapy of glioblastomas. Researchers in the lab first were able to show in glioblastoma cell lines that a drug called NVP-BEZ235, which is in clinical trials for other solid tumors, can also inhibit two key DNA repair enzymes, DNA-PKcs and ATM, which are crucial for NHEJ and HR, respectively. While the drug alone had limited effect, when combined with radiation therapy, the tumor cells could not quickly repair their DNA, stalling their growth.

While excited by the initial findings in cell lines, researchers remained cautious because previous efforts to identify DNA repair inhibitors had not succeded when used in living models – mice with glioblastomas. Drugs developed to treat brain tumors also must cross what’s known as the blood-brain-barrier in living models.

But the NVP-BEZ235 drug could successfully cross the blood-brain-barrier, and when administered to mice with glioblastomas and combined with radiation, the tumor growth in mice was slowed and the mice survived far longer – up to 60 days compared to approximately 10 days with the drug or radiation therapy alone. These findings were published in the March 1 issue of Clinical Cancer Research.

“The consequence is striking,” said Dr. Burma. “If you irradiate the tumors, nothing much happens because they grow right through radiation. Give the drug alone, and again, nothing much happens. But when you give the two together, tumor growth is delayed significantly. The drug has a very striking synergistic effect when given with radiation.”

The combination effect is important because the standard therapy for glioblastomas in humans is radiation therapy, so finding a drug that improves the effectiveness of radiation therapy could have profound clinical importance eventually. For example, such drugs may permit lower doses of X-rays and gamma rays to be used for traditional therapies, thereby causing fewer side effects.

“Radiation is still the mainstay of therapy, so we have to have something that will work with the mainstay of therapy,” Dr. Burma said.

While the findings provide proof that the concept of “radiosensitizing” glioblastomas works in mouse models, additional research and clinical trials will be needed to demonstrate whether the combination of radiation with DNA repair inhibitors would be effective in humans, Dr. Burma cautioned.

“Double-strand DNA breaks are a double-edged sword,” he said. “On one hand, they cause cancer. On the other, we use ionizing radiation and chemotherapy to cause double-strand breaks to treat the disease.”

Another recent publication from his lab highlights this apparent paradox by demonstrating how radiation can actually trigger glioblastomas in mouse models. This research, supported by NASA, is focused on understanding cancer risks from particle radiation, the type faced by astronauts on deep-space missions and now being used in cutting-edge cancer therapies such as proton and carbon ion therapy.

Dr. Burma’s lab uses the high-tech facilities and large particle accelerator of the NASA Space Radiation Laboratory at the Brookhaven National Laboratory in New York to generate heavy ions, which can be used to irradiate glioblastoma-prone mice to test both the cancer-inducing potential of particle radiation as well as its potential therapeutic use.

“Heavy particles cause dense tracks of damage, which are very hard to repair,” Dr. Burma noted. “With gamma or X-rays, which are used in medical therapy, the damage is diffuse and is repaired within a day. If you examine a mouse brain irradiated with heavy particles, the damage is repaired slowly and can last for months.”

These findings, published March 17 in Oncogene, suggest that glioblastoma risk from heavier particles is much higher compared to that from gamma or X-rays. This study is relevant to the medical field, since ionizing radiation, even low doses from CT scans, have been reported to increase the risk of brain tumors, Dr. Burma said.