Neuroscience

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Posts tagged brain cancer

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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)

Filed under glioblastoma brain cancer stem cells glycolysis genetics neurology neuroscience science

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Researchers Identify Genetic Signature of Deadly Brain Cancer

A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas – the most common form of malignant brain cancer. The findings, which appear in the journal Cell Reports, provide scientists with rich new potential set of targets to treat the disease.

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“This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumor progression,” said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. “By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention.”

As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumors known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective. 

Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumors.

Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.

Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes – cells that support the function of neurons – and oligodendrocytes – cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.

While Goldman’s group’s work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.

Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.

Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique “signature” that identified the tumor progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.

“One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it,” said Goldman. 

The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly overexpressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signaling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked – or knocked down – the expression of this gene, the tumor cells ceased growing, and implanted tumors shrank. 

“This study gives us a blueprint to develop new therapies,” said Goldman. “We can now devise a strategy to systematically and rationally analyze – and eliminate – glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy.  And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumors, regardless of the stage at which we initiate treatment.”

(Source: urmc.rochester.edu)

Filed under glioblastomas brain cancer stem cells progenitor cells tumor progression science

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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.

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.

Filed under glioblastoma cells brain tumor cold atmospheric plasma brain cancer neuroscience science

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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 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.

Filed under brain cancer glioblastoma glioma ATM kinase inhibitor ataxia telangiectasia neurobiology neuroscience science

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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."

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."

Filed under NeuroBlate brain tumor glioblastoma brain cancer MRI laser system neurology neuroscience science

94 notes

Brain Cancer Treatment Using Genetic Material from Bone Marrow Cells In a first-of-its-kind experiment using microvesicles generated from mesenchymal bone marrow cells (MSCs) to treat cancer, neurological researchers at Henry Ford Hospital have discovered a novel approach for treatment of tumors. Specifically, the research team found that introducing genetic material produced by MSCs significantly reduced a particularly resistant form of malignant brain tumor in living lab rats. “This is the first foray of its type in experimental cancer therapy, and it represents a highly novel and potentially effective treatment,” says Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute and vice chairman of the Department of Neurology at Henry Ford Hospital. The research is published in the current issue Cancer Letters. “I think this is an important and very novel approach for the treatment of cancers, and in this particular case the treatment of glioma,” says Dr. Chopp. “We have been at the forefront of developing microRNAs as a means to treat disease, such as cancer and neurological injury. “This study shows it is effective in the living brain, and may even lend itself to specific cancer therapy, customized for the individual patient,” Chopp adds. Chopp and his colleagues focused their efforts on glioma, by far the most common type of malignant brain tumor and one with a notably poor prognosis for survival. Tumor cells were surgically implanted in the brains of anesthetized male lab rats and allowed to grow for five days. The tumors then were injected with exosomes containing molecules of a microRNA called miR-146b – found in earlier Henry Ford research to have a strong effect on glioma cells. Exosomes are microscopic “lipid bubbles” that once were thought to carry and get rid of “old” proteins that were no longer needed by the body. After they were more recently found to also carry RNA, whole new fields of study were suggested, including groundbreaking work by Henry Ford researchers. In the rat study, Dr. Chopp and his colleagues used MSC bone marrow cells to produce the exosomes containing the miR-146b they injected into the cancerous tumors. Five days after this treatment, the rats were euthanized and their brains were removed, prepared for study and examined. Tumor size was measured using computer software. “We found that one injection of exosomes containing miR-146b five days after tumor implantation led to a significant reduction in tumor volume at 10 days after implant,” Chopp says. “Our data suggest that miR-146b elicits an anti-tumor effect in the rat brain, and that MSCs can be used as a ‘factory’ to generate exosomes genetically altered to contain miR-146b to effectively treat tumor.” (Image: iStock)

Brain Cancer Treatment Using Genetic Material from Bone Marrow Cells

In a first-of-its-kind experiment using microvesicles generated from mesenchymal bone marrow cells (MSCs) to treat cancer, neurological researchers at Henry Ford Hospital have discovered a novel approach for treatment of tumors.

Specifically, the research team found that introducing genetic material produced by MSCs significantly reduced a particularly resistant form of malignant brain tumor in living lab rats.

“This is the first foray of its type in experimental cancer therapy, and it represents a highly novel and potentially effective treatment,” says Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute and vice chairman of the Department of Neurology at Henry Ford Hospital.

The research is published in the current issue Cancer Letters.

“I think this is an important and very novel approach for the treatment of cancers, and in this particular case the treatment of glioma,” says Dr. Chopp. “We have been at the forefront of developing microRNAs as a means to treat disease, such as cancer and neurological injury.

“This study shows it is effective in the living brain, and may even lend itself to specific cancer therapy, customized for the individual patient,” Chopp adds.

Chopp and his colleagues focused their efforts on glioma, by far the most common type of malignant brain tumor and one with a notably poor prognosis for survival.

Tumor cells were surgically implanted in the brains of anesthetized male lab rats and allowed to grow for five days.

The tumors then were injected with exosomes containing molecules of a microRNA called miR-146b – found in earlier Henry Ford research to have a strong effect on glioma cells.

Exosomes are microscopic “lipid bubbles” that once were thought to carry and get rid of “old” proteins that were no longer needed by the body. After they were more recently found to also carry RNA, whole new fields of study were suggested, including groundbreaking work by Henry Ford researchers.

In the rat study, Dr. Chopp and his colleagues used MSC bone marrow cells to produce the exosomes containing the miR-146b they injected into the cancerous tumors.

Five days after this treatment, the rats were euthanized and their brains were removed, prepared for study and examined. Tumor size was measured using computer software.

“We found that one injection of exosomes containing miR-146b five days after tumor implantation led to a significant reduction in tumor volume at 10 days after implant,” Chopp says. “Our data suggest that miR-146b elicits an anti-tumor effect in the rat brain, and that MSCs can be used as a ‘factory’ to generate exosomes genetically altered to contain miR-146b to effectively treat tumor.”

(Image: iStock)

Filed under bone marrow cells brain tumours brain cancer glioma animal model neuroscience science

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Using Fat to Fight Brain Cancer In laboratory studies, Johns Hopkins researchers say they have found that stem cells from a patient’s own fat may have the potential to deliver new treatments directly into the brain after the surgical removal of a glioblastoma, the most common and aggressive form of brain tumor. The investigators say so-called mesenchymal stem cells (MSCs) have an unexplained ability to seek out damaged cells, such as those involved in cancer, and may provide clinicians a new tool for accessing difficult-to-reach parts of the brain where cancer cells can hide and proliferate anew. The researchers say harvesting MSCs from fat is less invasive and less expensive than getting them from bone marrow, a more commonly studied method. Results of the Johns Hopkins proof-of-principle study are described online in the journal PLOS ONE. “The biggest challenge in brain cancer is the migration of cancer cells. Even when we remove the tumor, some of the cells have already slipped away and are causing damage somewhere else,” says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine. “Building off our findings, we may be able to find a way to arm a patient’s own healthy cells with the treatment needed to chase down those cancer cells and destroy them. It’s truly personalized medicine.” For their test-tube experiments, Quinones-Hinojosa and his colleagues bought human MSCs derived from both fat and bone marrow, and also isolated and grew their own stem cell lines from fat removed from two patients. Comparing the three cell lines, they discovered that all proliferated, migrated, stayed alive and kept their potential as stem cells equally well. This was an important finding, Quinones-Hinojosa says, because it suggests that a patient’s own fat cells might work as well as any to create cancer-fighting cells. The MSCs, with their ability to home in on cancer cells, might be able to act as a delivery mechanism, bringing drugs, nanoparticles or some other treatment directly to the cells. Quinones-Hinojosa cautions that while further studies are under way, it will be years before human trials of MSC delivery systems can begin. Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed — from any number of locations in the body — a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to carry drugs or other treatments. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells. Currently, standard treatments for glioblastoma are chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 18 months of survival after diagnosis. Glioblastoma tumor cells are particularly nimble, migrating across the entire brain and establishing new tumors. This migratory capability is thought to be a key reason for the low cure rate of this tumor type. “Essentially these MSCs are like a ‘smart’ device that can track cancer cells,” Quinones-Hinojosa says. Quinones-Hinojosa says it’s unclear why MSCs are attracted to glioblastoma cells, but they appear to have a natural affinity for sites of damage in the body, such as a wound. MSCs, whether derived from bone marrow or fat, have been studied in animal models to treat trauma, Parkinson’s disease, ALS and other diseases.

Using Fat to Fight Brain Cancer

In laboratory studies, Johns Hopkins researchers say they have found that stem cells from a patient’s own fat may have the potential to deliver new treatments directly into the brain after the surgical removal of a glioblastoma, the most common and aggressive form of brain tumor.

The investigators say so-called mesenchymal stem cells (MSCs) have an unexplained ability to seek out damaged cells, such as those involved in cancer, and may provide clinicians a new tool for accessing difficult-to-reach parts of the brain where cancer cells can hide and proliferate anew. The researchers say harvesting MSCs from fat is less invasive and less expensive than getting them from bone marrow, a more commonly studied method.

Results of the Johns Hopkins proof-of-principle study are described online in the journal PLOS ONE.

“The biggest challenge in brain cancer is the migration of cancer cells. Even when we remove the tumor, some of the cells have already slipped away and are causing damage somewhere else,” says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine. “Building off our findings, we may be able to find a way to arm a patient’s own healthy cells with the treatment needed to chase down those cancer cells and destroy them. It’s truly personalized medicine.”

For their test-tube experiments, Quinones-Hinojosa and his colleagues bought human MSCs derived from both fat and bone marrow, and also isolated and grew their own stem cell lines from fat removed from two patients. Comparing the three cell lines, they discovered that all proliferated, migrated, stayed alive and kept their potential as stem cells equally well.

This was an important finding, Quinones-Hinojosa says, because it suggests that a patient’s own fat cells might work as well as any to create cancer-fighting cells. The MSCs, with their ability to home in on cancer cells, might be able to act as a delivery mechanism, bringing drugs, nanoparticles or some other treatment directly to the cells. Quinones-Hinojosa cautions that while further studies are under way, it will be years before human trials of MSC delivery systems can begin.

Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed — from any number of locations in the body — a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to carry drugs or other treatments. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells.

Currently, standard treatments for glioblastoma are chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 18 months of survival after diagnosis. Glioblastoma tumor cells are particularly nimble, migrating across the entire brain and establishing new tumors. This migratory capability is thought to be a key reason for the low cure rate of this tumor type.

“Essentially these MSCs are like a ‘smart’ device that can track cancer cells,” Quinones-Hinojosa says.

Quinones-Hinojosa says it’s unclear why MSCs are attracted to glioblastoma cells, but they appear to have a natural affinity for sites of damage in the body, such as a wound. MSCs, whether derived from bone marrow or fat, have been studied in animal models to treat trauma, Parkinson’s disease, ALS and other diseases.

Filed under brain tumor brain cancer glioblastoma stem cells mesenchymal stem cells neuroscience science

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New chemical probe provides tool to investigate role of malignant brain tumor domains In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease. “Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James. Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou. “Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James. Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state. In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.

New chemical probe provides tool to investigate role of malignant brain tumor domains

In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease.

“Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James.

Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou.

“Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James.

Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state.

In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.

Filed under brain tumor brain cancer gene expression proteins medicine neuroscience science

51 notes

People who carry a “G” instead of an “A” at a specific spot in their genetic code have roughly a six-fold higher risk of developing certain types of brain tumors, a Mayo Clinic and University of California, San Francisco study has found. The findings, published online in the journal Nature Genetics, could help researchers identify people at risk of developing certain subtypes of gliomas which account for about 20 percent of new brain cancers diagnosed annually in the U.S. and may lead to better surveillance, diagnosis and treatment. Researchers still have to confirm whether the spot is the source of tumors, but if it’s not, “it is pretty close,” says senior author Robert Jenkins, M.D., Ph.D., a pathologist at the Mayo Clinic Cancer Center. “Based on our findings, we are already starting to think about clinical tests that can tell patients with abnormal brain scans what kind of tumor they have, just by testing their blood.”

People who carry a “G” instead of an “A” at a specific spot in their genetic code have roughly a six-fold higher risk of developing certain types of brain tumors, a Mayo Clinic and University of California, San Francisco study has found. The findings, published online in the journal Nature Genetics, could help researchers identify people at risk of developing certain subtypes of gliomas which account for about 20 percent of new brain cancers diagnosed annually in the U.S. and may lead to better surveillance, diagnosis and treatment.

Researchers still have to confirm whether the spot is the source of tumors, but if it’s not, “it is pretty close,” says senior author Robert Jenkins, M.D., Ph.D., a pathologist at the Mayo Clinic Cancer Center. “Based on our findings, we are already starting to think about clinical tests that can tell patients with abnormal brain scans what kind of tumor they have, just by testing their blood.”

Filed under brain brain cancer genetics neuroscience science tumors genomics

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