Posts tagged glioblastoma
Articles and news from the latest research reports.
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.
There’s Life After Radiation for Brain Cells
Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment
Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.
“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”
The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.
In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.
In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.
“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”
His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.
(Source: hopkinsmedicine.org)
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.
Researchers develop new approach for studying deadly brain cancer
Human glioblastoma multiforme, one of the most common, aggressive and deadly forms of brain cancer, is notoriously difficult to study. Scientists have traditionally studied cancer cells in petri dishes, which have none of the properties of the brain tissues in which these cancers grow, or in expensive animal models.
Now a team of engineers has developed a three-dimensional hydrogel that more closely mimics conditions in the brain. In a paper in the journal Biomaterials, the researchers describe the new material and their approach, which allows them to selectively tune up or down the malignancy of the cancer cells they study.
The new hydrogel is more versatile than other 3-D gels used for growing glioma (brain cancer) cells in part because it allows researchers to change individual parameters – the gel’s stiffness, for example, or the presence of molecular signals that can influence cancer growth – while minimally altering its other characteristics, such as porosity.
Being able to adjust these traits individually will help researchers tease out important features associated with the initial growth of a tumor as well as its response to clinical therapies, said University of Illinois chemical and biomolecular engineering professor Brendan Harley, who led the study with postdoctoral researcher Sara Pedron and undergraduate student Eftalda Becka. Harley is an affiliate of the Institute for Genomic Biology at Illinois.
The researchers found that they could increase or decrease the malignancy of glioma cells in their hydrogel simply by adding hyaluronic acid, a naturally occurring carbohydrate found in many tissues, especially the brain.
Hyaluronic acid (HA) is a key component of the extracellular matrix that provides structural and chemical support to cells throughout the body. HA contributes to cell proliferation and cell migration, and local changes in HA levels have been implicated in tumor growth.
“Hyaluronic acid is one of the major building blocks in the brain,” Harley said. “The structure of a newly forming brain tumor has some of this HA within it, but there’s also a lot of the HA in the brain surrounding the tumor.”
Previous studies have used hydrogels made out of nothing but hyaluronic acid to study gliomas, Harley said. “The problem there is that HA is structurally not very strong.” It also is difficult to adjust the amount of HA that the glioma cells are exposed to if their environment is 100 percent HA, he said.
In the new study, Pedron observed how glioma cells behaved in two different hydrogels – one based on methacrylated gelatin (GelMA) and the other using a more conventional polyethylene glycol (PEG) biomaterial. These two materials vary in one important trait: GelMA is a naturally derived material that contains adhesive sites that allow cells to latch onto it; synthetic PEG does not.
“The purpose of having these two systems was to isolate the effect of HA on glioma cells,” Pedron said. If changing HA levels produced different effects in different gels, that would indicate that the gels were contributing to those effects, she said.
Instead, Harley and Pedron found that additions of HA to glioma cells had “very similar” effects in both materials. Adding too little or too much HA led to reduced malignancy, while incorporating just enough HA led to significantly enhanced malignancy. This held true for multiple types of glioblastoma multiforme cells. This suggests that “it’s the HA itself that is likely the cause for this malignant change,” Harley said.
“If you have a material that allows you to selectively tune up or down malignancy, that will allow you to ask lots of questions about treatment methods for more malignant or less malignant forms of glioma. It also will allow scientists to try to get a response that’s closer to what you see in the body,” he said.
“If you talk to pathologists, they’ll say a biomaterial will never allow you to grow a full brain tumor, which is probably true,” Harley said. “But it’s realistic to think that a well-designed biomaterial will allow you to study aspects of glioma growth and treatment in a way that’s much richer than simply looking in a petri dish and much more accessible than trying to study tumor development within the brain itself.”
Nano Drug Crosses Blood-Brain Tumor Barrier, Targets Brain Tumor Cells and Blood Vessels
An experimental drug in early development for aggressive brain tumors can cross the blood-brain tumor barrier, kill tumor cells and block the growth of tumor blood vessels, according to a study led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The laboratory and animal study also shows how the agent, called SapC-DOPS, targets tumor cells and blood vessels. The findings support further development of the drug as a novel treatment for brain tumors.
Glioblastoma multiforme is the most common and aggressive form of brain cancer, with a median survival of about 15 months. A major obstacle to improving treatment for the 3,470 cases of the disease expected in the United States this year is the blood-brain barrier, the name given to the tight fit of cells that make up the blood vessels in the brain. That barrier protects the brain from toxins in the blood but also keeps drugs in the bloodstream from reaching brain tumors.
“Few drugs have the capacity to cross the tumor blood-brain barrier and specifically target tumor cells,” says principal investigator Balveen Kaur, PhD, associate professor of neurological surgery and chief of the Dardinger Laboratory of Neurosciences at the OSUCCC – James. “Our preclinical study indicates that SapC-DOPS does both and inhibits the growth of new tumor blood vessels, suggesting that this agent could one day be an important treatment for glioblastoma and other solid tumors.”
The findings were published in a recent issue of the journal Molecular Therapy.
SapC-DOPS (saposin-C dioleoylphosphatidylserine), is a nanovesicle drug that has shown activity in glioblastoma, pancreatic cancer and other solid tumors in preclinical studies. The nanovesicles fuse with tumor cells, causing them to self-destruct by apoptosis.
Key findings of the study, which used two brain-tumor models, include:
- SapC-DOPS binds with exposed patches of the phospholipid phosphatidylserine (PtdSer) on the surface of tumor cells;
- Blocking PtdSer on cells inhibited tumor targeting;
- SapC-DOPS strongly inhibited brain-tumor blood-vessel growth in cell and animal models, probably because these cells also have high levels of exposed PtdSer.
- Hypoxic cells were sensitized to killing by SapC-DOPS.
“Based on our findings, we speculate that SapC-DOPS could have a synergistic effect when combined with chemotherapy or radiation therapy, both of which are known to increase the levels of exposed PtdSer on cancer cells,” Kaur says.
(Source: cancer.osu.edu)
Brain-penetrating particle attacks deadly tumors
Scientists have developed a new approach for treating a deadly brain cancer that strikes 15,000 in the United States annually and for which there is no effective long-term therapy. The researchers, from Yale and Johns Hopkins, have shown that the approach extends the lives of laboratory animals and are preparing to seek government approval for a human clinical trial.
“We wanted to make a system that would penetrate into the brain and deliver drugs to a greater volume of tissue,” said Mark Saltzman, a biomedical engineer at Yale and principal investigator of the research. “Drugs have to get to tumor cells in order to work, and they have to be the right drugs.”
Results were published July 1 in the Proceedings of the National Academy of Sciences.
Glioblastoma multiforme is a malignant cancer originating in the brain. Median survival with standard care — surgery plus chemotherapy plus radiation — is just over a year, and the five-year survival rate is less than 10 percent.
Current methods of drug delivery have serious limitations. Oral and intravenously injected drugs have difficulty accessing the brain because of a biological defense known as the blood-brain barrier. Drugs released directly in the brain through implants can’t reach migrating tumor cells. And commonly used drugs fail to kill the cells primarily responsible for tumor development, allowing regrowth.
The researchers developed a new, ultra-small drug-delivery particle that more nimbly navigates brain tissue than do existing options. They also identified and tested an existing FDA-approved drug — a fungicide called dithiazanine iodide (DI) — and found that it can kill the most aggressive tumor-causing cells.
“This approach addresses limitations of other forms of therapy by delivering drugs directly to the area most needed, obviating systemic side-effects, and permitting the drug to reside for weeks,” said neurosurgeon Dr. Joseph M. Piepmeier, a member of the research team. Piepmeier leads clinical research for Yale Cancer Center’s brain tumor program.
The drug-loaded nanoparticles are administered in fluid directly to the brain through a catheter, bypassing the blood-brain barrier. The particles’ tiny size — their diameter is about 70 nanometers — facilitates movement within brain tissue. They release their drug load gradually, offering sustained treatment.
In tests on laboratory rats with human brain cancers, DI-loaded nanoparticles significantly increased median survival to 280 days, researchers report. Maximum median survival time for rats treated with other therapies was 180 days, and with no treatment, survival was 147 days. Tests on pigs established that the new drug-particle combination also diffuses deep into brains of large animals.
The nanoparticles are made of polymers, or strings of repeating molecules. Their size, ability to control release, and means of application help them permeate brain tissues.
Researchers screened more than 2,000 FDA-approved drugs in the hunt for candidates that would kill the cells most responsible for human tumor development, brain cancer stem cells. Overall, DI worked best.
The scientists believe the particles can be adapted to deliver other drugs and to treat other central nervous system diseases, they said.
The paper is titled “Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.”
Brain Cancer: Hunger for Amino Acids Makes It More Aggressive
An enzyme that facilitates the breakdown of specific amino acids makes brain cancers particularly aggressive. Scientists from the German Cancer Research Center (DKFZ) discovered this in an attempt to find new targets for therapies against this dangerous disease. They have reported their findings in the journal “Nature Medicine”.
To fuel phases of fast and aggressive growth, tumors need higher-than-normal amounts of energy and the molecular building blocks needed to build new cellular components. Cancer cells therefore consume a lot of sugar (glucose A number of tumors are also able to catabolize the amino acid glutamine, an important building block of proteins. A key enzyme in amino acid decomposition is isocitrate dehydrogenase (IDH). Several years ago, scientists discovered mutations in the gene coding for IDH in numerous types of brain cancer. Very malignant brain tumors called primary glioblastomas carry an intact IDH gene, whereas those that grow more slowly usually have a defective form.
“The study of the IDH gene currently is one of the most important diagnostic criteria for differentiating glioblastomas from other brain cancers that grow more slowly,” says Dr. Bernhard Radlwimmer from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). “We wanted to find out what spurs the aggressive growth of glioblastomas.” In collaboration with scientists from other institutes including Heidelberg University Hospital, Dr. Martje Tönjes and Dr. Sebastian Barbus from Radlwimmer’s team compared gene activity profiles from several hundred brain tumors. They aimed to find out whether either altered or intact IDH show further, specific genetic characteristics that might help explain the aggressiveness of the disease.
The researchers found a significant difference between the two groups in the highly increased activity of the gene for the BCAT1 enzyme, which in normal brain tissue is responsible for breaking down so-called branched-chain amino acids. However, Radlwimmer’s team discovered, only those tumor cells whose IDH gene is not mutated produce BCAT1. “This is not surprising, because as IDH breaks down amino acids, it produces ketoglutarate – a molecule which BCAT1 needs. This explains why BCAT1 is produced only in tumor cells carrying intact IDH. The two enzymes seem to form a kind of functional unit in amino acid catabolism,” says Bernhard Radlwimmer.
Glioblastomas are particularly dreaded because they aggressively invade the healthy brain tissue that surrounds them. When the researchers used a pharmacological substance to block BCAT1’s effects, the tumor cells lost their invasive capacity. In addition, the cells released less of the glutamate neurotransmitter. High glutamate release is responsible for severe neurological symptoms such as epileptic seizures, which are frequently associated with the disease. When transferred to mice, glioblastoma cells in which the BCAT1 gene had been blocked no longer grew into tumors.
“Altogether, we can see that overexpression of BCAT1 contributes to the aggressiveness of glioblastoma cells,” Radlwimmer says. The study suggests that the two enzymes, BCAT1 and IDH, cooperate in the decomposition of branched-chain amino acids. These protein building blocks appear to act as a “food source” that increases the cancer cells’ aggressiveness. Branched-chain amino acids also play a significant role in metabolic diseases such as diabetes. This is the first time that scientists have been able to show the role of these amino acids in the growth of malignant tumors.
“The good news,” sums up Radlwimmer, “is that we have found another target for therapies in BCAT1. In collaboration with Bayer Healthcare, we have already started searching for agents that might be specifically directed against this enzyme.” The researchers also plan to investigate whether BCAT1 expression may serve as an additional marker to diagnose the malignancy of brain cancer.
Metabolic Molecule Drives Growth Of Aggressive Brain Cancer
- Genomic research has shown that glioblastoma, the most dangerous type of brain cancer, has four subtypes.
- This study examines two of the subtypes and identifies an abnormal metabolic pathway that drives the aggressive growth of one of them.
- The findings could lead to targeted therapies for treating an aggressive form of glioblastoma.
A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified an abnormal metabolic pathway that drives cancer-cell growth in a particular glioblastoma subtype. The finding might lead to new therapies for a subset of patients with glioblastoma, the most common and lethal form of brain cancer.
The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.
This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.
The findings, published recently in the Proceedings of the National Academy of Sciences, show that high levels of the enzyme drive tumor growth.
“Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature,” says principal investigator Ichiro Nakano, MD, PhD, associate professor of neurosurgery at the OSUCCC – James. “This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients,” he says.
The National Cancer Institute estimates that 23,130 Americans will be diagnosed with brain and other nervous system tumors in 2013, and that 14,000 people will die of these malignancies. Glioblastoma accounts for about 15 percent of all brain tumors, is resistant to current therapies and has a survival as short as 15 months after diagnosis.
Little is known, however, about the metabolic pathways that drive the growth of individual glioblastoma subtypes – knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.
For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and pre-clinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.
Key technical findings include:
- Genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells compared to proneural stem cells;
- Mesenchymal glioma stem cells show significantly higher radiation resistance and high expression of DNA-repair genes;
- Radiation induces transformation of proneural glioma stem cells into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment; inhibiting the ALDH1 pathway reverses this resistance.
- Inhibiting ALDH1A3-mediated pathways slows the growth of mesenchymal glioma stem cells and might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature.
“Overall, our data suggest that a novel signaling mechanism underlies the transformation of proneural glioma stem cells to mesenchymal-like cells and their maintenance as stem-like cells,” Nakano says. Currently, their discoveries are in provision patent application, led by the Technology Licensing Office at University of Pittsburgh.
(Source: cancer.osu.edu)
New drug enhances radiation treatment for brain cancer in preclinical studies
A novel drug may help increase the effectiveness of radiation therapy for the most deadly form of brain cancer, report scientists at Virginia Commonwealth University Massey Cancer Center. In mouse models of human glioblastoma multiforme (GBM), the new drug helped significantly extend survival when used in combination with radiation therapy.
Recently published in the journal Clinical Cancer Research, the study provides the first preclinical evidence demonstrating that an ATM kinase inhibitor radiosensitizes gliomas. Gliomas are brain tumors that originate from glial cells, which provide support for nerve cells and help regulate the internal environment of the brain. ATM, or ataxia telangiectasia mutated, is an enzyme that helps repair DNA damage. The scientists used an experimental drug, KU-60019, to block the activation of ATM, which led to the enhanced destruction of the gliomas due to their reduced ability to repair the DNA damage caused by the radiation treatment. The new approach was particularly effective against gliomas that have a mutation in the p53 tumor suppressor gene, which accounts for approximately 30 percent of all glioma cases.
"Sadly, the average life expectancy of patients diagnosed with glioblastoma is just 12 to 15 months," says the study’s lead researcher Kristoffer Valerie, Ph.D., co-leader of the Radiation Biology and Oncology research program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. "By limiting the tumor’s ability to combat DNA damage caused by treatments such as radiation, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue."
Currently, GBM is treated with surgery, followed by chemotherapy and radiation therapy. Potentially, ATM kinase inhibitors like the one used in this study could enhance the effectiveness of some other cancer treatments that kill tumor cells by damaging DNA. The scientists chose radiation therapy in this study since it is already standard care and can be delivered to brain tumors with extreme accuracy, minimizing damage to surrounding healthy tissue.
"If these findings hold up in early phase clinical trials, we expect patients with p53 mutant gliomas to respond well to this treatment while showing few side effects. Also, we anticipate that this same treatment strategy could be effective for other cancers that are treated with DNA-damaging chemotherapies," says Valerie. "We are encouraged by these early findings and will continue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans."
This first, ‘proof-of-principle’ study is an important follow-up of a study published several years ago on KU-60019 by Valerie and his research team that demonstrated KU-60019’s superior efficacy, specificity and potency on glioma cells as compared to a predecessor ATM inhibitor.
Valerie and his team are conducting additional studies examining the effects of KU-60019 and other ATM kinase inhibitors on gliomas, including studies that combine ATM kinase inhibitors with a type of drug known as a PARP inhibitor to increase the effectiveness of the treatment. PARP inhibitors block the action of poly ADP ribose polymerase (PARP), an enzyme that also aids in the repair of DNA damage. The researchers believe that combining an ATM kinase inhibitor with a PARP inhibitor may cause a condition referred to as “synthetic lethality,” which arises when the functions of at least two interacting genes are simultaneously inhibited, which, in turn, leads to tumor cell death.
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."