Posts tagged brain tumor
Articles and news from the latest research reports.
Biomaterial-delivered chemotherapy could provide final blow to brain tumours
A polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumours, researchers at The University of Nottingham have discovered.
Their study, published in the journal PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks.
The targeted nature of the therapy could also reduce the toxic effects of chemotherapy drugs on healthy parts of the body, potentially reducing the debilitating side-effects that many patients experience after cancer treatment.
Patient survival
Dr Ruman Rahman, of the University’s Children’s Brain Tumour Research Centre (CBTRC), who led the study, said: “Our system is an innovative method of drug delivery for the treatment of brain tumours and is intended to be administered immediately after surgery by the operating neurosurgeon.
“Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumours, prolonged patient survival and reduced morbidity.”
Brain tumours are the major cause of cancer-related death in children and adults up to the age of 40. Most relapses occur when surgeons are unable to remove all of the cancerous cells during surgery – something which can be particularly challenging in very young children and babies and by the very nature of a type of adult brain cancer called glioblastoma.
Although alternative systems for delivery of drugs directly to the brain have been developed, they are used infrequently because their success has been limited. This new drug delivery system is the first that can be moulded to the shape of the brain tumour cavity and the first to deliver several different drugs over a clinically meaningful period of time.
The Nottingham polymer formulation is made from two types of micro-particles called PLGA and PEG and has been developed and patented by leading tissue engineer Professor Kevin Shakesheff, based in the University’s School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.
Unique properties
The unique properties of the polymer lie in its ability to set into a rigid structure only when it reaches body temperature (37 degrees), a feature perfectly tailored for use in medical therapies. It was originally developed as a scaffold on to which new bone cells could be grown to speed up the knitting back together of broken bones.
Dr Ruman Rahman at the CBTRC and Dr Cheryl Rahman from the School of Pharmacy spotted the potential for the polymer to deliver chemotherapy drugs directly to patients’ brain tumours. The work was performed at the CBTRC with neurosurgeon Mr Stuart Smith and neuro-oncologist Professor Richard Grundy. The cavity left by the removal of a tumour would be lined with the polymer while in paste form, which would start to solidify and gradually release the chemotherapy drugs after the incision has been closed. This would directly target any residual cells not initially removed during surgery.
In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.
To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumour cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep’s brain from an abattoir by moulding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.
The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumour patients who have undergone surgery.
Robust material
The team also dealt with concerns that the material could disintegrate and release its chemotherapy contents too quickly during the subsequent radiotherapy which many cancer patients undergo following surgery. By placing the biomaterial loaded with chemotherapy drugs into a head cavity of a medical training dummy and subjecting it to the same duration and intensity of radiotherapy used for brain tumour patients they were able to successfully demonstrate the robust integrity of the structure.
Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumours to test whether animals with the drug-loaded polymers survive longer. The team are also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.
As the research used a biomaterial and chemotherapy drugs already approved for medical use, many of the usual ethical approval hurdles to allow further investigation have already been cleared.
The first clinical test, anticipated in 3 years’ time, will be to devise a multi-centre phase 0 clinical trial which would involve testing the therapy on a small number of patients for whom other clinical treatments have not been successful and would otherwise only be offered palliative care.
“This is a very exciting development and holds considerable promise for the treatment of malignant brain tumours in the near future” commented Professor Grundy, Co-Director of the CBTRC.
(Source: nottingham.ac.uk)
A new approach to treating brain cancer
A new experimental approach to treating a type of brain cancer called medulloblastoma has been developed by researchers at Sanford-Burnham. The method targets cancer stem cells—the cells that are critical for maintaining tumor growth—and halts their ability to proliferate by inhibiting enzymes that are essential for tumor progression. The process destroys the ability of the cancer cells to grow and divide, paving the way for a new type of treatment for patients with this disease.
The research team, led by Robert Wechsler-Reya, Ph.D., professor in Sanford-Burnham’s NCI-Designated Cancer Center and director of the Tumor Initiation and Maintenance Program, discovered that the medulloblastoma cancer cells responsible for tumor growth and progression (called cancer stem cells or tumor-propagating cells—TPCs) divide more quickly than normal cells. Correspondingly, they have higher levels of certain enzymes that regulate the cell cycle (Aurora and Polo-like kinases). By using small-molecule inhibitors to stop the action of these enzymes, the researchers were able to block the growth of tumor cells from mice as well as humans. The research findings are described in an online paper published today by Cancer Research.
“One tumor can have many different types of cells in it, and they can grow at different rates. By targeting fast-growing TPCs with cell-cycle inhibitors, we have developed a new route to assault medulloblastoma. In this study, we have shown that cell-cycle inhibitors essentially block medulloblastoma tumor progression by halting TPC expansion, and have opened the window to preventing cancer recurrence,” said Wechsler-Reya.
The team’s first set of experiments used a mouse model for medulloblastoma. In-vitro studies of mouse tumor cells showed that cell-cycle inhibitors caused tumor cell death. In vivo, mice that were treated with the inhibitor had smaller tumors that weighed less compared to mice that were not treated, essentially halting the progression of the tumor.
The second set of experiments used human medulloblastoma cells. When the researchers treated these human tumor cells with cell-cycle inhibitors, they also observed a significant reduction in tumor growth and progression.
Finally, when the scientists combined cell-cycle inhibitors with treatments currently used for medulloblastoma, they found that the combination worked together to produce results that were greater than either inhibitor alone.
“These results strongly support an approach to treatment that combines current therapies with cell-cycle inhibitors to treat medulloblastoma. Our hope is that the combination of these inhibitors will prevent tumor progression and drug resistance, and improve the overall effectiveness of current treatment options. We look forward to clinical studies in human medulloblastoma patients as well as other cancers that are suitable for this approach,” Wechsler-Reya said.
(Source: beaker.sanfordburnham.org)
New laser-based tool could dramatically improve the accuracy of brain tumor surgery
Imaging technique tells tumor tissue from normal tissue, could be used in operating room for real-time guidance of surgery
A new laser-based technology may make brain tumor surgery much more accurate, allowing surgeons to tell cancer tissue from normal brain at the microscopic level while they are operating, and avoid leaving behind cells that could spawn a new tumor.
This image of a human glioblastoma brain tumor in the brain of a mouse was made with stimulated Raman scattering, or SRS, microscopy. The technique allows the tumor (blue) to be easily distinguished from normal tissue (green) based on faint signals emitted by tissue with different cellular structures.
In a new paper, featured on the cover of the journal Science Translational Medicine, a team of University of Michigan Medical School and Harvard University researchers describes how the technique allows them to “see” the tiniest areas of tumor cells in brain tissue.
They used this technique to distinguish tumor from healthy tissue in the brains of living mice — and then showed that the same was possible in tissue removed from a patient with glioblastoma multiforme, one of the most deadly brain tumors.
Now, the team is working to develop the approach, called SRS microscopy, for use during an operation to guide them in removing tissue, and test it in a clinical trial at U-M. The work was funded by the National Institutes of Health.
A need for improvement in tumor removal
On average, patients diagnosed with glioblastoma multiforme live only 18 months after diagnosis. Surgery is one of the most effective treatments for such tumors, but less than a quarter of patients’ operations achieve the best possible results, according to a study published last fall in the Journal of Neurosurgery.
“Though brain tumor surgery has advanced in many ways, survival for many patients is still poor, in part because surgeons can’t be sure that they’ve removed all tumor tissue before the operation is over,” says co-lead author Daniel Orringer, M.D., a lecturer in the U-M Department of Neurosurgery who has worked with the Harvard team since a chance meeting with a team member during his U-M residency.
On the left, the view of the brain that neurosurgeons currently see during an operation using bright-field microscopy. On the right, an SRS microscopy view of the same area of brain - in this case, a mouse brain that has had human brain tumor tissue transplanted into it. SRS might someday allow surgeons to see this same view of patients’ brains.
“We need better tools for visualizing tumor during surgery, and SRS microscopy is highly promising,” he continues. “With SRS we can see something that’s invisible through conventional surgical microscopy.”
The SRS in the technique’s name stands for stimulated Raman scattering. Named for C.V. Raman, one of the Indian scientists who co-discovered the effect and shared a 1930 Nobel Prize in physics for it, Raman scattering involves allows researchers to measure the unique chemical signature of materials.
In the SRS technique, they can detect a weak light signal that comes out of a material after it’s hit with light from a non-invasive laser. By carefully analyzing the spectrum of colors in the light signal, the researchers can tell a lot about the chemical makeup of the sample.
Over the past 15 years, Sunney Xie, Ph.D., of the Department of Chemistry and Chemical Biology at Harvard University – the senior author of the new paper — has advanced the technique for high-speed chemical imaging. By amplifying the weak Raman signal by more than 10,000 times, it is now possible to make multicolor SRS images of living tissue or other materials. The team can even make 30 new images every second — the rate needed to create videos of the tissue in real time.
Seeing the brain’s microscopic architecture
A multidisciplinary team of chemists, neurosurgeons, pathologists and others worked to develop and test the tool. The new paper is the first time SRS microscopy has been used in a living organism to see the “margin” of a tumor – the boundary area where tumor cells infiltrate among normal cells. That’s the hardest area for a surgeon to operate – especially when a tumor has invaded a region with an important function.
As the images in the paper show, the technique can distinguish brain tumor from normal tissue with remarkable accuracy, by detecting the difference between the signal given off by the dense cellular structure of tumor tissue, and the normal healthy grey and white matter.
The authors suggest that SRS microscopy may be as accurate for detecting tumor as the approach currently used in brain tumor diagnosis – called H&E staining.
This image shows the same areas of brain, imaged with SRS microscopy (left) and conventional H&E staining, which is the current technique used to diagnose brain tumors at the tissue level. The research suggests that SRS microscopy could be as accurate as H&E staining in allowing doctors to see tumors - without having to remove tissue or inject dyes into the patient.
The paper contains data from a test that pitted H&E staining directly against SRS microscopy. Three surgical pathologists, trained in studying brain tissue and spotting tumor cells, had nearly the same level of accuracy no matter which images they studied. But unlike H&E staining, SRS microscopy can be done in real time, and without dyeing, removing or processing the tissue.
Next steps: A smaller laser, a clinical trial
The current SRS microscopy system is not yet small or stable enough to use in an operating room. The team is collaborating with a start-up company formed by members of Xie’s group, called Invenio Imaging Inc., which is developing a laser to perform SRS through inexpensive fiber-optic components. The team is also working with AdvancedMEMS Inc. to reduce the size of the probe that makes the images possible.
A validation study, to examine tissue removed from consenting U-M brain tumor patients, may begin as soon as next year.
(Source: uofmhealth.org)
Researchers Find Promising Therapeutic Target for Hard-To-Treat Brain Tumor
Specific protein found in nearly all high-grade meningiomas
Johns Hopkins researchers say they have found a specific protein in nearly 100 percent of high-grade meningiomas — the most common form of brain tumor — suggesting a new target for therapies for a cancer that does not respond to current chemotherapy.
Importantly, the investigators say, the protein — NY-ESO-1 — is already at the center of a clinical trial underway at the National Cancer Institute. That trial is designed to activate the immune systems of patients with other types of tumors that express the protein, training the body to attack the cancer and eradicate it.
“Typically there is a lag time before a laboratory finding like this leads to a clear path forward to help patients. But in this case, since there is already a clinical trial underway, we have a chance of helping people sooner rather than later,” says Gregory J. Riggins, M.D., Ph.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and the senior author of the study published online in the journal Cancer Immunology Research.
In the NCI trial, NY-ESO-1 is found in a much smaller percentage of tumors than Riggins and his team found in high-grade meningioma, suggesting that for the brain cancer, the target would be potentially more significant.
Most low-grade meningiomas located in easy-to-reach locations can be treated successfully with surgery and radiation. But more atypical, higher-grade tumors are much more difficult to eradicate and are deadlier.
Riggins and his colleagues, including Gilson S. Baia, Ph.D., and Otavia L. Caballero, M.D., Ph.D., set out to find cancer antigens in meningioma. Cancer antigens are proteins expressed in tumors but not in healthy cells, making them good targets for chemical or immune system attack. They looked specifically at 37 cancer/testis (CT) genes, which are not found in normal cells in the body except in germ cells and cells cordoned off in the testicles or, in some cases, ovaries.
CT genes are activated, however, in various cancers. While they are seen as “foreign” by the body’s immune system, they are often locked behind the sophisticated defense system that cancers use to evade attack by immune cells. Finding a way to get the immune system to see these protein antigens, however, could allow for the body to recognize the invasion and go after the cancer cells. Various approaches are being used to do that, including vaccines and a system involving removing T-cells from the body and reprogramming them before returning them and setting them loose on the cancer cells.
The Johns Hopkins researchers took tissue from 18 different meningioma samples, removed the genetic material and protein and checked at what levels the 37 different genes were turned on. The gene that is the blueprint for the NY-ESO-1 protein was turned on more frequently than any other, in five of the 18 patient samples.
Then they analyzed NY-ESO-1 expression in a larger group of 110 meningioma tissue samples. They found NY-ESO-1 in 108 of them. The more expression in the sample, they also determined, the higher the tumor grade. The higher levels of NY-ESO-1 expressed also correlated with significantly lower disease-free and overall survival rates in the patients they came from.
The NCI trial originally began in melanoma patients. NY-ESO-1 is expressed in roughly one-third of melanomas as well as approximately one-third of breast, prostate, lung, ovarian, thyroid and bladder cancers, as well as sarcomas. Riggins and his team did not find the protein in glioblastoma, the deadliest form of brain cancer.
He calls the fact that the NCI trial could now include meningioma patients a “stroke of luck.”
“If that therapy did not exist, there would be a lot of work that would have to be done to convince people to pursue this,” Riggins says. “Our goal is to get something that works to the patients. This puts us well on our way.”
(Source: hopkinsmedicine.org)
MR images showing a patient with recurrent glioblastoma responding to anti-angiogenic therapy by reduction on abnormal tumor vessel calibers and a change in the direction of the vessel vortex curve estimated from a combined gradient-echo (GE) and spin-echo (SE) MR signal readout. The change from a predominantly counter-clockwise vessel vortex direction at baseline (days -5 and -1) to a predominantly clockwise vessel vortex direction during anti-angiogenic therapy (days 1, 28, 56 and 112) indicates a dramatic transformation in vascular morphology during anti-angiogenic therapy and resulting in increased overall survival. Credit: Kyrre E. Emblem
New MR analysis technique reveals brain tumor response to anti-angiogenesis therapy
A new way of analyzing data acquired in MR imaging appears to be able to identify whether or not tumors are responding to anti-angiogenesis therapy, information that can help physicians determine the most appropriate treatments and discontinue ones that are ineffective. In their report receiving online publication in Nature Medicine, investigators from the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH), describe how their technique, called vessel architectural imaging (VAI), was able to identify changes in brain tumor blood vessels within days of the initiation of anti-angiogenesis therapy.
"Until now the only ways of obtaining similar data on the blood vessels in patients’ tumors were either taking a biopsy, which is a surgical procedure that can harm the patients and often cannot be repeated, or PET scanning, which provides limited information and exposes patients to a dose of radiation,” says Kyrre Emblem, PhD, of the Martinos Center, lead and corresponding author of the report. “VAI can acquire all of this information in a single MR exam that takes less than two minutes and can be safely repeated many times.”
Previous studies in animals and in human patients have shown that the ability of anti-angiogenesis drugs to improve survival in cancer therapy stems from their ability to “normalize” the abnormal, leaky blood vessels that usually develop in a tumor, improving the perfusion of blood throughout a tumor and the effectiveness of chemotherapy and radiation. In the deadly brain tumor glioblastoma, MGH investigators found that anti-angiogenesis treatment alone significantly extends the survival of some patients by reducing edema, the swelling of brain tissue. In the current report, the MGH team uses VAI to investigate how these drugs produce their effects and which patients benefit.
Advanced MR techniques developed in recent years can determine factors like the size, radius and capacity of blood vessels. VAI combines information from two types of advanced MR images and analyzes them in a way that distinguishes among small arteries, veins and capillaries; determines the radius of these vessels and shows how much oxygen is being delivered to tissues. The MGH team used VAI to analyze MR data acquired in a phase 2 clinical trial – led by Tracy Batchelor, MD, director of Pappas Center for Neuro-Oncology at MGH and a co-author of the current paper – of the anti-angiogenesis drug cediranib in patients with recurrent glioblastoma. The images had been taken before treatment started and then 1, 28, 56, and 112 days after it was initiated.
In some patients, VAI identified changes reflecting vascular normalization within the tumors – particularly changes in the shape of blood vessels – after 28 days of cediranib therapy and sometimes as early as the next day. Of the 30 patients whose data was analyzed, VAI indicated that 10 were true responders to cediranib, whereas 12 who had a worsening of disease were characterized as non-responders. Data from the remaining 8 patients suggested stabilization of their tumors. Responding patients ended up surviving six months longer than non-responders, a significant difference for patients with an expected survival of less than two years, Emblem notes. He adds that quickly identifying those whose tumors don’t respond would allow discontinuation of the ineffective therapy and exploration of other options.
Gregory Sorensen, MD, senior author of the Nature Medicine report, explains, “One of the biggest problems in cancer today is that we do not know who will benefit from a particular drug. Since only about half the patients who receive a typical anti-cancer drug benefit and the others just suffer side effects, knowing whether or not a patient’s tumor is responding to a drug can bring us one step closer to truly personalized medicine – tailoring therapies to the patients who will benefit and not wasting time and resources on treatments that will be ineffective.” Formerly with the Martinos Center, Sorensen is now with Siemens Healthcare.
Study co-author Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Oncology, adds, “This is the most compelling evidence yet of vascular normalization with anti-angiogenic therapy in cancer patients and how this concept can be used to select patients likely to benefit from these therapies.”
Lead author Emblem notes that VAI may help further improve understanding of how abnormal tumor blood vessels change during anti-angiogenesis treatment and could be useful in the treatment of other types of cancer and in vascular conditions like stroke. He and his colleagues are also exploring whether VAI can identify which glioblastoma patients are likely to respond to anti-angiogenesis drugs even before therapy is initiated, potentially eliminating treatment destined to be ineffective. A postdoctoral research fellow at the Martinos Center at the time of the study, Emblem is now a principal investigator at Oslo University Hospital in Norway and maintains an affiliation with the Martinos Center.
Study Reveals Genes That Drive Brain Cancer
About 15 percent of glioblastoma patients could receive personalized treatment with drugs currently used in other cancers
A team of researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center has identified 18 new genes responsible for driving glioblastoma multiforme, the most common—and most aggressive—form of brain cancer in adults. The study was published August 5, 2013, in Nature Genetics.
“Cancers rely on driver genes to remain cancers, and driver genes are the best targets for therapy,” said Antonio Iavarone, MD, professor of pathology and neurology at Columbia University Medical Center and a principal author of the study.
“Once you know the driver in a particular tumor and you hit it, the cancer collapses. We think our study has identified the vast majority of drivers in glioblastoma, and therefore a list of the most important targets for glioblastoma drug development and the basis for personalized treatment of brain cancer.”
Personalized treatment could be a reality soon for about 15 percent of glioblastoma patients, said Anna Lasorella, MD, associate professor of pediatrics and of pathology & cell biology at CUMC.
“This study—together with our study from last year, Research May Lead to New Treatment for Type of Brain Cancer—shows that about 15 percent of glioblastomas are driven by genes that could be targeted with currently available FDA-approved drugs,” she said. “There is no reason why these patients couldn’t receive these drugs now in clinical trials.”
New Bioinformatics Technique Distinguishes Driver Genes from Other Mutations
In any single tumor, hundreds of genes may be mutated, but distinguishing the mutations that drive cancer from mutations that have no effect has been a longstanding problem for researchers.
An analysis of all gene mutations in nearly 140 brain tumors has uncovered most of the genes responsible for driving glioblastoma. The analysis found 18 new driver genes (labeled red), never before implicated in glioblastoma and correctly identified the 15 previously known driver genes (labeled blue). The graphs show mutated genes that are commonly found in varying numbers in glioblastoma (left), that frequently contain insertions (middle), and that frequently contain deletions (right). Genes represented by blue dots in the graphs were statistically most likely to be driver genes. Image: Raul Rabadan/Columbia University Medical Center.
The Columbia team used a combination of high throughput DNA sequencing and a new method of statistical analysis to generate a short list of driver candidates. The massive study of nearly 140 brain tumors sequenced the DNA and RNA of every gene in the tumors to identify all the mutations in each tumor. A statistical algorithm designed by co-author Raul Rabadan, PhD, assistant professor of biomedical informatics and systems biology, was then used to identify the mutations most likely to be driver mutations. The algorithm differs from other techniques to distinguish drivers from other mutations in that it considers not only how often the gene is mutated in different tumors, but also the manner in which it is mutated.
“If one copy of the gene in a tumor is mutated at a single point and the second copy is mutated in a different way, there’s a higher probability that the gene is a driver,” Dr. Iavarone said.
The analysis identified 15 driver genes that had been previously identified in other studies—confirming the accuracy of the technique—and 18 new driver genes that had never been implicated in glioblastoma.
Significantly, some of the most important candidates among the 18 new genes, such as LZTR1 and delta catenin, were confirmed to be driver genes in laboratory studies involving cancer stem cells taken from human tumors and examined in culture, as well as after they had been implanted into mice.
A New Model for Personalized Cancer Treatment
Because patients’ tumors are powered by different driver genes, the researchers say that a complicated analysis will be needed for personalized glioblastoma treatment to become a reality. First, all the genes in a patient’s tumor must be sequenced and analyzed to identify its driver gene.
“In some tumors it’s obvious what the driver is; but in others, it’s harder to figure out,” said Dr.Iavarone.
Once the candidate driver is identified, it must be confirmed in laboratory tests with cancer stem cells isolated from the patient’s tumor.
About 15 percent of glioblastoma driver genes can be targeted with currently available drugs, suggesting that personalized treatment for some patients may be possible in the near future. Personalized therapy for glioblastoma patients could be achieved by isolating the most aggressive cells from the patient’s tumor and identifying the driver gene responsible for the tumor’s growth (different tumors will be driven by different genes). Drugs can then be tested on the isolated cells to find the most promising candidate. In this image, the gene mutation driving the malignant tumor has been replaced with the normal gene, transforming malignant cells back into normal brain cells. Image: Anna Lasorella.
“Cancer stem cells are the tumor’s most aggressive cells and the critical cellular targets for cancer therapies,” said Dr. Lasorella. “Drugs that prove successful in hitting driver genes in cancer stem cells and slowing cancer growth in cell culture and animal models would then be tried in the patient.”
Personalized Treatment Already Possible for Some Patients
For 85 percent of the known glioblastoma drivers, no drugs that target them have yet been approved.
But the Columbia team has found that about 15 percent of patients whose tumors are driven by certain gene fusions, FDA-approved drugs that target those drivers are available.
The study found that half of these patients have tumors driven by a fusion between the gene EGFR and one of several other genes. The fusion makes EGFR—a growth factor already implicated in cancer—hyperactive; hyperactive EGFR drives tumor growth in these glioblastomas.
“When this gene fusion is present, tumors become addicted to it—they can’t live without it,” Dr. Iavarone said. “We think patients with this fusion might benefit from EGFR inhibitors that are already on the market. In our study, when we gave the inhibitors to mice with these human glioblastomas, tumor growth was strongly inhibited.”
Other patients have tumors that harbor a fusion of the genes FGFR (fibroblast growth factor receptor) and TACC (transforming acidic coiled-coil), first reported by the Columbia team last year. These patients may benefit from FGFR kinase inhibitors. Preliminary trials of these drugs (for treatment of other forms of cancer) have shown that they have a good safety profile, which should accelerate testing in patients with glioblastoma.
Suspicions confirmed: Common cause for brain tumors in children
An overactive signaling pathway is a common cause in cases of pilocytic astrocytoma, the most frequent type of brain cancer in children. This was discovered by a network of scientists coordinated by the German Cancer Research Center (as part of the International Cancer Genome Consortium, ICGC). In all 96 cases studied, the researchers found defects in genes involved in a particular pathway. Hence, drugs can be used to help affected children by blocking components of the signaling cascade. The project is funded by the German Cancer Aid (Deutsche Krebshilfe) and the Federal Ministry of Education and Research (BMBF). The findings are published in the latest issue of the journal “Nature Genetics”.
Brain cancer is the primary cause of cancer mortality in children. Even in cases when the cancer is cured, young patients suffer from the stress of a treatment that can be harmful to the developing brain. In a search for new target structures that would create more gentle treatments, cancer researchers are systematically analyzing all alterations in the genetic material of these tumors. This is the mission of the PedBrain consortium, which was launched in 2010. Led by Professor Stefan Pfister from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), the PedBrain researchers have now published the results of the first 96 genome analyses of pilocytic astrocytomas.
Pilocytic astrocytomas are the most common childhood brain tumors. These tumors usually grow very slowly. However, they are often difficult to access by surgery and cannot be completely removed, which means that they can recur. The disease may thus become chronic and have debilitating effects for affected children.
In previous work, teams of researchers led by Professor Dr. Stefan Pfister and Dr. David Jones had already discovered characteristic mutations in a major proportion of pilocytic astrocytomas. All of the changes involved a key cellular signaling pathway known as the MAPK signaling cascade. MAPK is an abbreviation for “mitogen-activated protein kinase.” This signaling pathway comprises a cascade of phosphate group additions (phosphorylation) from one protein to the next – a universal method used by cells to transfer messages to the nucleus. MAPK signaling regulates numerous basic biological processes such as embryonic development and differentiation and the growth and death of cells.
“A couple of years ago, we had already hypothesized that pilocytic astrocytomas generally arise from a defective activation of MAPK signaling,” says David Jones, first author of the publication. “However, in about one fifth of the cases we had not initially discovered these mutations. In a whole-genome analysis of 96 tumors we have now discovered activating defects in three other genes involved in the MAPK signaling pathway that have not previously been described in astrocytoma.”
“Aside from MAPK mutations, we do not find any other frequent mutations that could promote cancer growth in the tumors. This is a very clear indication that overactive MAPK signals are necessary for a pilocytic astrocytoma to develop,” says study director Stefan Pfister. The disease thus is a prototype for rare cancers that are based on defects in a single biological signaling process.
In total, the genomes of pilocytic astrocytomas contain far fewer mutations than are found, for example, in medulloblastomas, a much more malignant pediatric brain tumor. This finding is in accordance with the more benign growth behavior of astrocytomas. The number of mutations increases with the age of the affected individuals.
About one half of pilocytic astrocytomas develop in the cerebellum, the other 50 percent in various other brain regions. Cerebellar astrocytomas are genetically even more homogenous than other cases of the disease: In 48 out of 49 cases that were studied, the researchers found fusions between the BRAF gene, a central component of the MAPK signaling pathway, and various other fusion partners.
“The most important conclusion from our results,” says study director Stefan Pfister, “is that targeted agents for all pilocytic astrocytomas are potentially available to block an overactive MAPK signaling cascade at various points. We might thus in the future be able to also help children whose tumors are difficult to access by surgery.”
Immune system to fight brain tumours
Research at Lund University in Sweden gives hope that one of the most serious types of brain tumour, glioblastoma multiforme, could be fought by the patients’ own immune system. The tumours are difficult to remove with surgery because the tumour cells grow into the surrounding healthy brain tissue. A patient with the disease therefore does not usually survive much longer than a year after the discovery of the tumour.
The team has tested different ways of stimulating the immune system, suppressed by the tumour, with a ‘vaccine’. The vaccine is based on tumour cells that have been genetically modified to start producing substances that activate the immune system. The modified tumour cells (irradiated so that they cannot divide and spread the disease) have been combined with other substances that form part of the body’s immune system.
The treatment has produced good results in animal experiments: 75 per cent of the rats that received the treatment were completely cured of their brain tumours.
“Human biology is more complicated, so we perhaps cannot expect such good results in patients. However, bearing in mind the poor prognosis patients receive today, all progress is important”, said doctoral student Sara Fritzell, part of the research group led by consultant Peter Siesjö.
She has previously tested combining the activation of the immune system with chemotherapy. When the chemotherapy was applied directly to the tumour site, the positive effects reinforced each other, and a huge 83 per cent of the mice survived.
“Our idea is in the future to give patients chemotherapy locally in conjunction with the operation to remove as much of the tumour as possible”, said Sara Fritzell.
Peter Siesjö is currently applying for permission to carry out a clinical study on stimulation of the immune system – with or without local chemotherapy – as a treatment for patients with glioblastoma multiforme.
(Source: lunduniversity.lu.se)
Cold plasma successful against brain cancer cells
For the first time, physicists from the Max Planck Institute for Extraterrestrial Physics (MPE), biologists and physicians demonstrated the synergistic effect of cold atmospheric plasma - a partly ionized gas - and chemo therapy on aggressive brain tumour cells. Laboratory tests showed that the proliferation of glioblastoma cells – the most common and aggressive brain tumour in adults – is arrested and that even resistant cell populations become sensitive to treatment with chemo therapy if pre-treated with cold atmospheric plasma. This could be the first step on the way to a new combination therapy, providing new hope for fighting this lethal cancer.
If someone is diagnosed with the type of brain tumour called glioblastoma, the prospects are dire: median survival is just a bit over one year, and less than 16% of the patients survive more than three years. It is still unknown how this cancer is triggered – only a few rare genetic factors have been identified so far – and treatment remains largely palliative, i.e. trying to alleviate the symptoms and prolonging the life of the patient. The standard therapy proceeds in three steps: Guided by an MRT scan, the tumour is removed surgically, followed by radiation and chemo therapy. But even if the treatment is successful initially, there is a high likelihood of relapse.
A recently developed new kind of treatment could offer some hope. Cold atmospheric plasma, or CAP for short, has already proven to successfully inactivate bacteria, fungi, viruses and spores, while healthy tissue remains largely unaffected. Healthcare applications such as the sterilization of surgical instruments, skin and wound disinfection paved its way into medical care. Recently also CAP sources were developed which show anti-cancer properties.
"For many patients the regular treatment is just not effective, because the brain tumours contain sub-populations for which chemo therapy does not work,” says Julia Zimmermann, who manages the Plasma Healthcare group at MPE. “So we were particularly interested to see if the CAP would be effective against these resistant tumour cells – and indeed it worked!”
For the study, the researchers used Glioblastoma cells and grew them in cell culture dishes, where they could be subjected to various combinations of treatments. For both normal and resistant tumour cell lines, the growth of the cells was more inhibited after the plasma treatment compared to the chemo therapy alone. The largest effect could be obtained for a short application time of 120 seconds; such an additional step could be easily incorporated into the clinical treatment if an appropriate plasma device can be developed.
The researchers also found that CAP stops the cell cycle and that the individual cells lose their ability to clone themselves. A combined therapy of both - CAP treatment and chemo therapy – showed the most promising results, where the amount of chemotherapeutic needed to achieve the same result as with chemo therapy alone is strongly reduced. So far, no resistance towards CAP treatment was observed. The study also showed that even those cell lines that originally were resistant against the chemo therapy drug became sensitive again after the pre-application of CAP.
“In particular, also resistant cell populations could be treated effectively with CAP, which means that there is now hope to find a therapy for the patients with a poor prognosis, i.e. those with resistant cells in the tumour,” explains Julia Köritzer, lead author of the study. Such a treatment option for resistant cells is urgently needed, because about 40% of the patients do not profit from chemo therapy. She adds: “It is a first step, now we have to further investigate the effects gained in the cell culture and integrate them for the application.”
Though, even if there is still a long way ahead before CAP can actually be used in the hospital, it offers a promising new possibility. Eventually it could be applied after surgery to treat the tissue around the extracted tumour, where some cancerous cells might have been left behind, preventing the cancer from reappearing. Devices similar to an endoscope are currently under development.
New minimally invasive, MRI-guided laser treatment for brain tumor found to be promising in study
The first-in-human study of the NeuroBlate™ Thermal Therapy System finds that it appears to provide a new, safe and minimally invasive procedure for treating recurrent glioblastoma (GBM), a malignant type of brain tumor. The study, which appears April 5 in the Journal of Neurosurgery online, was written by lead author Andrew Sloan, MD, Director of Brain Tumor and Neuro-Oncology Center at University Hospitals (UH) Case Medical Center and Case Comprehensive Cancer Center, who also served as co-Principal Investigator, as well as Principal Investigator Gene Barnett, MD, Director of the Brain Tumor and Neuro-Oncology Center at Cleveland Clinic and Case Comprehensive Cancer Center, and colleagues from UH, Cleveland Clinic, Cleveland Clinic Florida, University of Manitoba and Case Western Reserve University.
NeuroBlate™ is a device that “cooks” brain tumors in a controlled fashion to destroy them. It uses a minimally invasive, MRI-guided laser system to coagulate, or heat and kill, brain tumors. The procedure is conducted in an MRI machine, enabling surgeons to plan, steer and see in real-time the device, the heat map of the area treated by the laser and the tumor tissue that has been coagulated.
"This technology is unique in that it allows the surgeon not only to precisely control where the treatment is delivered, but the ability to visualize the actual effect on the tissue as it is happening," said Dr. Sloan. "This enables the surgeon to adjust the treatment continuously as it is delivered, which increases precision in treating the cancer and avoiding surrounding healthy brain tissue."
The study was a Phase I clinical trial investigating the safety and performance of NeuroBlate™ (formerly known as AutoLITT™), a specially-designed laser probe system. The FDA gave the system’s developer Monteris Medical and the Case Comprehensive Cancer Center, (comprised of the UH Case Medical Center, Cleveland Clinic, and Case Western Reserve University School of Medicine), an investigatory device exemption (IDE) to study the system in patients with GBMs. The device has recently been cleared by the FDA due, in part, to the results of the study.
The paper describes the treatment of the first 10 patients with this technology. These patients, who had a median age of 55, had tumors which were diagnosed to be inoperable or “high risk” for open surgical resection because of their location close to vital areas in the brain, or difficult to access with conventional surgery.
"Overall the NeuroBlate™ procedure was well-tolerated," said Dr. Sloan. "All 10 patients were alert and responsive within one to two hours post-operatively and nine out of the 10 patients were ambulatory within hours. Response and survival was also nearly 10 ½ months, better than expected for patients with such advanced disease."
"Previous attempts using less invasive approaches such as brachytherapy and stereotactic radiosurgery have proven ineffective in recent meta-analysis and randomized trials," said Dr. Barnett. "However, unlike therapies using ionizing radiation, NeuroBlate™ therapy results in tumor death at the time of the procedure. A larger national study will be developed, as a result of this initial success."