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.”

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.

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)

Personalized Brain Mapping Technique Preserves Function Following Brain Tumor Surgery

Neurosurgeons can visualize important pathways in the brain using an imaging technique called diffusion tensor imaging (DTI), to better adapt brain tumor surgeries and preserve language, visual and motor function while removing cancerous tissue. In the latest issue of Neurosurgical Focus, researchers from the Perelman School of Medicine at the University of Pennsylvania review research showing that this ability to visualize relevant white matter tracts during glioma resection surgeries can improve accuracy and, in some groups, significantly extend survival (median survival of 21.2 months) compared to cases where DTI was not used  (median survival of 14 months).

"We can view the brain from the inside out now, with 3D images detailing connectivity within the brain, making a virtual intraoperative map," said senior author Steven Brem, MD, professor of Neurosurgery, chief of the Division of Neurosurgical Oncology and co-director of the Penn Brain Tumor Center. "Penn is at the forefront of a major shift in the field - we now have such detail about each individual’s brain tumor - combining diffusion tensor imaging and advanced imaging with the entire personalized diagnostics analysis available for all brain tumor patients at Penn Medicine."

Diffusion tensor imaging (DTI) provides a rendering of axon pathways, by tracking water molecules in the brain as they travel in a direction parallel to axonal fibers, in a 3D model known as “the diffusion tensor.” The diffusion tensor directly represents the direction of water and indirectly represents the orientation of white matter fibers. The colorful images, captured as part of an 8 minute sequence during an MRI, show representations of clusters of axon fibers, where each color indicates a direction of travel, and offer a glimpse of the interwoven communication superhighways of the brain.

"The DTI images can be overlaid with structural and functional MRI images, providing a hybrid map showing topography layered with a road map," said Neurosurgery resident Kalil Abdullah, MD, lead author of the paper. "This rendering gives us increased clarity to visualize important white matter tracts in the brain and adapt our surgical approaches to each person’s case. Rather than focusing on solely taking the tumor out, we can avoid damage to healthy tissue and preserve important pathways responsible for speech, vision and motor function."

Relying heavily on the expertise of radiologists who process and analyze the DTI images, including Ronald L. Wolf, MD, PhD, associate professor of Radiology at Penn, the research on DTI is being translated into clinical practice to guide surgical procedures. Further research efforts are targeted at defining language deficits before surgery and following-up post-operatively to determine any changes or improvements following treatment based on the use of DTI.

Working collaboratively with colleagues in Penn’s departments of Neurosurgery, Neurology, Radiology, Radiation Oncology, Nursing, Pathology and Laboratory Medicine and the Abramson Cancer Center, the Penn Brain Tumor Center combines the latest imaging, biomarker and genetic tumor testing to provide a personalized treatment plan for all types of brain cancers. Brain tumors are among the first areas of interest for Penn’s Center for Personalized Diagnostics (CPD), a joint initiative by Penn Medicine’s Department of Pathology and Laboratory Medicine and the Abramson Cancer Center, which integrates Molecular Genetics, Pathology Informatics, and Genomic Pathology for individualized patient diagnoses and to elucidate cancer treatment options for physicians.

(Image: Swedish Research)