Posts tagged glioblastoma
Articles and news from the latest research reports.
New approach makes cancer cells explode
Researchers at Karolinska Institutet have discovered that a substance called Vacquinol-1 makes cells from glioblastoma, the most aggressive type of brain tumour, literally explode. When mice were given the substance, which can be given in tablet form, tumour growth was reversed and survival was prolonged. The findings are published in the journal Cell.
The established treatments that are available for glioblastoma include surgery, radiation and chemotherapy. But even if this treatment is given the average survival is just 15 months. It is therefore critical to find better treatments for malignant brain tumours.
Researchers at Karolinska Institutet and colleagues at Uppsala University have discovered an entirely new mechanism to kill tumour cells in glioblastoma. Researchers in an initial stage have exposed tumour cells to a wide range of molecules. If the cancer cells died, the molecule was considered of interest for further studies, which initially applied to over 200 kinds of molecules. Following extensive studies, a single molecule has been identified as being of particular interest. The researchers wanted to find out why it caused cancer cell death.
It was found that the molecule gave the cancer cells an uncontrolled vacuolization, a process in which the cell carries substances from outside the cell into its interior. This carrying process is made via the vacuoles, which can roughly be described as blisters or bags consisting of cell membranes. The process is similar to what was behind last year’s Nobel Prize in physiology or medicine, the discovery that describes how cellular vesicles move things from the interior of the cell to its surface.
Cell membranes collapsed
When cancer cells were filled with a large amount of vacuoles, the cell membranes, the outer wall of the cell, collapsed and the cell simply exploded and necrotized.
“This is an entirely new mechanism for cancer treatment. A possible medicine based on this principle would therefore attack the glioblastoma in an entirely new way. This principle may also work for other cancer diseases, we have not really explored this yet,” says Patrik Ernfors, professor of tissue biology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
Researchers made mice that had human glioblastoma cells transplanted ingest the substance for five days. The average survival was about 30 days for the control group that did not receive the substance. Of those who received the substance six of eight mice were still alive after 80 days. The study was then considered of such interest that the scientific journal wanted to publish the article immediately.
“We now want to try to take this discovery in basic research through preclinical development and all the way to the clinic. The goal is to get into a phase 1 trial,” says Patrik Ernfors.
Stopping tumours in their path
Glioblastoma (GBM) is the most common and deadly form of primary malignant brain cancer accounting for approximately 15% of all brain tumours and occurring mostly in adults between the ages of 45 and 70. The aggressive recurrent nature of this cancer is only temporarily contained by combined surgery, chemotherapy and radiation treatment. The recurrence of GBM is usually fatal, resulting in an average patient survival time of less than two years. A new study from the Montreal Neurological Institute and Hospital – The Neuro - at McGill University, published in Nature Communications, identifies two specific key players in the growth of GBM.
A GBM tumour contains a complex combination of different cell types, including ‘stem-like’ cells that are able to initiate brain tumour growth, even when present in very small numbers. These cells, known as brain-tumour initiating cells (BTICs), are believed to be among the cells that can re-initiate GBM if they are not completely eradicated through surgery, radiation and chemotherapy. Thus, BTICs represent an important therapeutic target for GBM treatment strategies.
“We wanted to find out how GBM-derived BTICs are able to initiate a tumour with the ultimate goal of preventing the re-growth of this deadly form of brain cancer,” says Dr. Stefano Stifani, neuroscientist at The Neuro and senior investigator on the paper. “What we found is that by impairing the activity of two transcription factors (proteins that control gene expression), termed FOXG1 and TLE, we can significantly reduce the ability of BTICs to give rise to brain tumours.” The researchers studied brain tumour growth in an in vivo mouse model using human GBM-derived BTICs. This approach provides what is called an in vivo environment that closely resembles the original human brain tumours. The demonstration that the FOXG1 and TLE proteins are important for the tumour-forming ability of human GBM-derived BTICs has long-term implications because FOXG1 and TLE control the expression of numerous genes. Identifying the genes whose expression is controlled by FOXG1 and TLE is expected to provide further information on the mechanisms involved in GBM tumourigenesis. In the long term, researchers hope to identify multiple important regulators, in order to find new potential therapeutic targets to impair the tumourigenic ability of BTICs.
“The implication of transcription factors FOXG1 and TLE in the tumour-forming ability of BTICs opens the door to possible strategies to block tumour growth – a major advance in the fight against GBM.”
(Image: ALAMY)
Biomaterial-delivered chemotherapy could provide final blow to brain tumours
A polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumours, researchers at The University of Nottingham have discovered.
Their study, published in the journal PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks.
The targeted nature of the therapy could also reduce the toxic effects of chemotherapy drugs on healthy parts of the body, potentially reducing the debilitating side-effects that many patients experience after cancer treatment.
Patient survival
Dr Ruman Rahman, of the University’s Children’s Brain Tumour Research Centre (CBTRC), who led the study, said: “Our system is an innovative method of drug delivery for the treatment of brain tumours and is intended to be administered immediately after surgery by the operating neurosurgeon.
“Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumours, prolonged patient survival and reduced morbidity.”
Brain tumours are the major cause of cancer-related death in children and adults up to the age of 40. Most relapses occur when surgeons are unable to remove all of the cancerous cells during surgery – something which can be particularly challenging in very young children and babies and by the very nature of a type of adult brain cancer called glioblastoma.
Although alternative systems for delivery of drugs directly to the brain have been developed, they are used infrequently because their success has been limited. This new drug delivery system is the first that can be moulded to the shape of the brain tumour cavity and the first to deliver several different drugs over a clinically meaningful period of time.
The Nottingham polymer formulation is made from two types of micro-particles called PLGA and PEG and has been developed and patented by leading tissue engineer Professor Kevin Shakesheff, based in the University’s School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.
Unique properties
The unique properties of the polymer lie in its ability to set into a rigid structure only when it reaches body temperature (37 degrees), a feature perfectly tailored for use in medical therapies. It was originally developed as a scaffold on to which new bone cells could be grown to speed up the knitting back together of broken bones.
Dr Ruman Rahman at the CBTRC and Dr Cheryl Rahman from the School of Pharmacy spotted the potential for the polymer to deliver chemotherapy drugs directly to patients’ brain tumours. The work was performed at the CBTRC with neurosurgeon Mr Stuart Smith and neuro-oncologist Professor Richard Grundy. The cavity left by the removal of a tumour would be lined with the polymer while in paste form, which would start to solidify and gradually release the chemotherapy drugs after the incision has been closed. This would directly target any residual cells not initially removed during surgery.
In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.
To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumour cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep’s brain from an abattoir by moulding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.
The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumour patients who have undergone surgery.
Robust material
The team also dealt with concerns that the material could disintegrate and release its chemotherapy contents too quickly during the subsequent radiotherapy which many cancer patients undergo following surgery. By placing the biomaterial loaded with chemotherapy drugs into a head cavity of a medical training dummy and subjecting it to the same duration and intensity of radiotherapy used for brain tumour patients they were able to successfully demonstrate the robust integrity of the structure.
Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumours to test whether animals with the drug-loaded polymers survive longer. The team are also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.
As the research used a biomaterial and chemotherapy drugs already approved for medical use, many of the usual ethical approval hurdles to allow further investigation have already been cleared.
The first clinical test, anticipated in 3 years’ time, will be to devise a multi-centre phase 0 clinical trial which would involve testing the therapy on a small number of patients for whom other clinical treatments have not been successful and would otherwise only be offered palliative care.
“This is a very exciting development and holds considerable promise for the treatment of malignant brain tumours in the near future” commented Professor Grundy, Co-Director of the CBTRC.
(Source: nottingham.ac.uk)
Incurable Brain Cancer Gene Is Silenced
Gene regulation technology increases survival rates in mice with glioblastoma
Glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy and kills approximately 13,000 Americans a year, is aggressive and incurable. Now a Northwestern University research team is the first to demonstrate delivery of a drug that turns off a critical gene in this complex cancer, increasing survival rates significantly in animals with the deadly disease.
Image: Researchers combined gold nanoparticles (in yellow) with small interfering RNAs (in green) to knock down an oncogene that is overexpressed in glioblastoma.
The novel therapeutic, which is based on nanotechnology, is small and nimble enough to cross the blood-brain barrier and get to where it is needed — the brain tumor. Designed to target a specific cancer-causing gene in cells, the drug simply flips the switch of the troublesome oncogene to “off,” silencing the gene. This knocks out the proteins that keep cancer cells immortal.
In a study of mice, the nontoxic drug was delivered by intravenous injection. In animals with GBM, the survival rate increased nearly 20 percent, and tumor size was reduced three to four fold, as compared to the control group. The results are published today (Oct. 30) in Science Translational Medicine.
“This is a beautiful marriage of a new technology with the genes of a terrible disease,” said Chad A. Mirkin, a nanomedicine expert and a senior co-author of the study. “Using highly adaptable spherical nucleic acids, we specifically targeted a gene associated with GBM and turned it off in vivo. This proof-of-concept further establishes a broad platform for treating a wide range of diseases, from lung and colon cancers to rheumatoid arthritis and psoriasis.”
Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering.
Glioblastoma expert Alexander H. Stegh came to Northwestern University in 2009, attracted by the University’s reputation for interdisciplinary research, and within weeks was paired up with Mirkin to tackle the difficult problem of developing better treatments for glioblastoma.
Help is critical for patients with GBM: The median survival rate is 14 to 16 months, and approximately 16,000 new cases are reported in the U.S. every year.
In their research partnership, Mirkin had the perfect tool to tackle the deadly cancer: spherical nucleic acids (SNAs), new globular forms of DNA and RNA, which he had invented at Northwestern in 1996, and which are nontoxic to humans. The nucleic acid sequence is designed to match the target gene.
And Stegh had the gene: In 2007, he and colleagues identified the gene Bcl2Like12 as one that is overexpressed in glioblastoma tumors and related to glioblastoma’s resistance to conventional therapies.
“My research group is working to uncover the secrets of cancer and, more importantly, how to stop it,” said Stegh, a senior co-author of the study. “Glioblastoma is a very challenging cancer, and most chemo-therapeutic drugs fail in the clinic. The beauty of the gene we silenced in this study is that it plays many different roles in therapy resistance. Taking the gene out of the picture should allow conventional therapies to be more effective.”
Stegh is an assistant professor in the Ken and Ruth Davee Department of Neurology at the Northwestern University Feinberg School of Medicine and an investigator in the Northwestern Brain Tumor Institute.
The power of gene regulation technology is that a disease with a genetic basis can be attacked and treated if scientists have the right tools. Thanks to the Human Genome Project and genomics research over the last two decades, there is an enormous number of genetic targets; having the right therapeutic agents and delivery materials has been the challenge.
“The RNA interfering-based SNAs are a completely novel approach in thinking about cancer therapy,” Stegh said. “One of the problems is that we have large lists of genes that are somehow disregulated in glioblastoma, but we have absolutely no way of targeting all of them using standard pharmacological approaches. That’s where we think nanomaterials can play a fundamental role in allowing us to implement the concept of personalized medicine in cancer therapy.”
Stegh and Mirkin’s drug for GBM is specially designed to target the Bcl2Like12 gene in cancer cells. Key is the nanostructure’s spherical shape and nucleic acid density. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. (The gold nanoparticle core is only 13 nanometers in diameter.) The RNA’s sequence is programmed to silence the disease-causing gene.
“The problems posed by glioblastoma and many other diseases are simply too big for one research group to handle,” said Mirkin, who also is the director of Northwestern’s International Institute for Nanotechnology. “This work highlights the power of scientists and engineers from different fields coming together to address a difficult medical issue.”
Mirkin first developed the nanostructure platform used in this study in 1996 at Northwestern, and the technology now is the basis of powerful commercialized and FDA-cleared medical diagnostic tools. This new development, however, is the first realization that the nanostructures injected into an animal naturally find their target in the brain and can deliver an effective payload of therapeutics.
The next step for the therapeutic will be to test it in clinical trials.
The nanostructures used in this study were developed in Mirkin’s lab on the Evanston campus and then used in cell and animal studies in Stegh’s lab on the Chicago campus.
(Source: northwestern.edu)
The Cancer Genome Atlas exposes more secrets of lethal brain tumor
Project delves deeply in genomics of 599 glioblastoma multiforme cases to better target disease
When The Cancer Genome Atlas launched its massively collaborative approach to organ-by-organ genomic analysis of cancers, the brain had both the benefit, and the challenge, of going first.
TCGA ganged up on glioblastoma multiforme (GBM), the most common and lethal of brain tumors, with more than 100 scientists from 14 institutions tracking down the genomic abnormalities that drive GBM.
Five years later, older and wiser, TCGA revisited glioblastoma, producing a broader, deeper picture of the drivers – and potential therapeutic targets – of the disease published in the Oct. 10 issue of Cell.
“The first paper in 2008 characterized glioblastoma in important new ways and illuminated the path for all TCGA organ studies that have followed,” said senior author Lynda Chin, M.D., professor and chair of Genomic Medicine and scientific director of the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.
“Our new study reflects major improvements in technology applied to many more tumor samples to more completely characterize the landscape of genomic alterations in glioblastoma,” said Chin, who was also co-senior author of the first paper while she was on the faculty of Dana-Farber Cancer Institute in Boston.
“Information generated by this unbiased, data-driven analysis presents new opportunities to discover genomics-based biomarkers, understand disease mechanisms and generate new hypotheses to develop better, targeted therapies,” Chin said.
About 23,000 new cases of GBM are predicted in the United States during 2013 and more than 14,000 people expected to die of the disease. Most patients die within 15 months of diagnosis.
Well of rich, detailed data will nurture better treatment
New information about genetic mutations, deletions and amplifications; gene expression and epigenetic regulation; structural changes due to chromosomal alterations, proteomic effects and the molecular networks that drive GBM make for a deep, broad dataset that will underpin research and clinical advances for years to come.
“Our main contribution is this tremendous resource for the GBM research community, which is already heavily relying on the earlier TCGA study,” said co-lead author Roeland Verhaak, Ph.D., assistant professor of Bioinformatics and Computational Biology at MD Anderson. “Whatever new treatments people come up with for GBM, I’m very confident that their discovery and development will in some way have benefited from this rich and detailed data set,” he said.
The Cell paper describes analysis of tumor samples and molecular data from 599 patients at 17 study sites. Detailed clinical information including treatment and survival was available for almost all cases
New targetable mutations
In addition to confirming significantly mutated genes discovered earlier, such as the tumor suppressors TP53, PTEN and RB1 and the oncogene PIK3CA, the analysis identified 61 new mutated genes. The most frequent mutations occurred in from 1.7 to 9 percent of cases.
Two of these, BRAF and FGFR, might have more immediate clinical relevance, Verhaak noted. MD Anderson neuro-oncologists are checking to see if patients have these mutations. Drugs are available to address those variations now, Verhaak said. The BRAF point mutation in GBM is the same commonly found in melanoma, which is treated by a new class of drugs.
More twists and turns for EGFR
The larger data set and an improved analytical algorithm allowed major refinement of gene amplification and deletion information. For example, common amplification events were found to occur more frequently than previously known, including amplification of the epidermal growth factor receptor (EGFR) on chromosome 7.
EGFR is both amplified and mutated frequently in GBM; yet therapeutic efforts targeting EGFR so far have failed. “We found EGFR is more frequently altered than we already thought,” Verhaak said.
Overall, the EGFR gene was mutated, rearranged, amplified or otherwise altered in 57 percent of tumors. Increased EGFR protein levels in GBM cells correlated with the many mechanisms of EGFR alteration, Verhaak said.
A treatment based on EGFR still has great potential, he noted. But strategies to target EGFR will need to address the likelihood that different alterations of EGFR might be present in the same tumor and affect the impact of targeted drugs.
Breaking GBM into molecular subtypes
Verhaak and other researchers in recent years have begun to classify GBM tumors by gene expression. Four such subgroups — neural, proneural, mesenchymal and classical — were further characterized by DNA methylation pattern, signaling pathway activity and by clinical measures such as survival and treatment response. Methylation of a gene turns it off.
Understanding the subgroups could establish biomarkers to guide treatment and identify new therapeutic targets.
The team found, for example, that the survival advantage of the proneural subtype depends on a specific DNA methylation pattern known as G-CIMP and that DNA methylation of the MGMT gene may serve as a biomarker of treatment response in the classical subtype.
(Source: mdanderson.org)
Researchers erase human brain tumor cells in mice
Working with mice, Johns Hopkins researchers have discovered that weeks of treatment with a repurposed FDA-approved drug halted the growth of — and ultimately left no detectable trace of — brain tumor cells taken from adult human patients.
The scientists targeted a mutation in the IDH1 gene first identified in human brain tumors called gliomas by a team of Johns Hopkins cancer researchers in 2008. This mutation was found in 70 to 80 percent of lower-grade and progressive forms of the brain cancer. The change occurs within a single spot along a string of thousands of genetic coding letters, and is disruptive enough to keep the seemingly innocuous protein from playing its role in converting glucose into energy. Instead, the mutation hijacks the protein to make a new molecule not normally found in the cell, which is apparently a linchpin in the process of forming and maintaining cancer cells.
Encouraged by the new findings, described online Sept. 16 in the open-access journal Oncotarget, the Johns Hopkins researchers say they want to work quickly to design a clinical trial to bring what they learned in mice to humans with gliomas. Despite the growing understanding of IDH1 mutant gliomas, the development of effective therapies has proven challenging, they say.
"Usually in the lab, we’re happy to see a drug slow down tumor growth," says Alexandra Borodovsky, a graduate student in the Cellular and Molecular Medicine Program at the Johns Hopkins University School of Medicine who performed the experiments. "We never expect tumors to regress, but that is exactly what happened here."
"This therapy has worked amazingly well in these mice," says study leader Gregory J. Riggins, M.D., Ph.D., a professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. "We have spoken with neurosurgeons here, and as soon as possible, we want to start discussing the parameters of a clinical trial to see if this will work in our patients as a follow-up to surgery."
The researchers caution that many treatments have cured cancers in mice, and then failed in humans.
The IDH1 gene, whose name stands for isocitrate dehydrogenase 1, produces an enzyme that regulates cell metabolism. Mutations, or changes in the DNA code, force the IDH1 gene to increase production of a flawed version of the enzyme. The flawed enzyme produces large amounts of an entirely new molecule, called 2-hydroxyglutarate. This molecule is believed to cause groups of atoms called methyl groups to latch onto the DNA strand.
Although methylation is a normal cellular process, when too many methyl groups glom onto the DNA, Riggins says, this can interfere with normal cell biology and eventually contribute to cancer formation and growth.
Borodovsky, Riggins and their colleagues — including Timothy A. Chan, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York — thought that a drug that could strip those methyl groups might be able to reverse the cancer process in those cancers with IDH1 mutations. They chose 5-azacytidine, which is approved to treat a pre-leukemia condition called myelodysplastic syndrome and is being tested on lung and other cancers at Johns Hopkins and elsewhere.
Riggins notes that one of the difficulties in developing treatments for IDH1 mutant brain cancers is finding a model in which to study them. Cell lines containing the IDH1 mutation are difficult to grow in the laboratory, for example. Borodovsky worked with Johns Hopkins neurosurgeons to obtain tumor cells from glioma patients likely to have IDH1 mutations and injected them under the skins of mice. She did this for months, before finally getting the tumor cells to grow.
Once the tumors grew, the researchers injected the mice with 5-azacytidine for 14 weeks and saw a dramatic reduction in growth and what appeared to be complete regression. Then they withdrew therapy. Seven weeks later, the tumors had not regrown. The researchers, however, said they do expect the tumors to regrow at some point, and are still monitoring the mice.
The type of tumor targeted by the researchers eventually progresses to a subtype of glioblastoma multiform — the deadliest form of brain cancer — known as progressive or secondary glioblastoma. They arise as a lower-grade glioma and are initially treated with surgery alone, but eventually they progress to the more lethal form of tumor. Survival is longer than with glioblastoma, but it is found in younger patients, those under the age of 50. While both types of tumor look the same at the end, they look very different at the molecular level, Riggins says, leading researchers to believe they may have a better chance at targeting the progressive tumors, which are more likely to have the IDH1 mutation.
Chan’s team at Sloan-Kettering simultaneously published a paper in Oncotarget, along with Borodovsky and Riggins, which describes similar results in a different animal model using a similar drug. This is further evidence that the strategy is a sound one, Riggins says.
(Source: eurekalert.org)
Researchers identify a switch that controls growth of most aggressive brain tumor cells
Researchers at UT Southwestern Medical Center have identified a cellular switch that potentially can be turned off and on to slow down, and eventually inhibit the growth of the most commonly diagnosed and aggressive malignant brain tumor.
Findings of their investigation show that the protein RIP1 acts as a mediator of brain tumor cell survival, either protecting or destroying cells. Researchers believe that the protein, found in most glioblastomas, can be targeted to develop a drug treatment for these highly malignant brain tumors. The study was published online Aug. 22 in Cell Reports.
"Our study identifies a new mechanism involving RIP1that regulates cell division and death in glioblastomas," said senior author Dr. Amyn Habib, associate professor of neurology and neurotherapeutics at UT Southwestern, and staff neurologist at VA North Texas Health Care System. "For individuals with glioblastomas, this finding identified a target for the development of a drug treatment option that currently does not exist."
In the study, researchers used animal models to examine the interactions of the cell receptor EGFRvIII and RIP1. Both are used to activate NFκB, a family of proteins that is important to the growth of cancerous tumor cells. When RIP1 is switched off in the experimental model, NFκB and the signaling that promotes tumor growth is also inhibited. Furthermore, the findings show that RIP1 can be activated to divert cancer cells into a death mode so that they self-destruct.
According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast-growing, treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas, and ependymomas. In many cases, survival is tied to novel clinical trial treatments and research that will lead to drug development.
(Source: eurekalert.org)
New System Uses Nanodiamonds to Deliver Chemotherapy Directly to Brain Tumors
Researchers at UCLA’s Jonsson Comprehensive Cancer Center have developed a new drug delivery system using nanodiamonds (NDs) that allows for direct application of chemotherapy to brain tumors with fewer harmful side effects and better cancer-killing efficiency than existing treatments.
The study was a collaboration between Dean Ho, professor, division of oral biology and medicine, division of advanced prosthodontics, and department of bioengineering and co-director of the Weintraub Center for Reconstructive Biotechnology at UCLA School of Dentistry and colleagues from the Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine.
Glioblastoma is the most common and lethal type of brain tumor. Despite treatment with surgery, radiation and chemotherapy, median survival time of patients with glioblastoma is less than 1.5 years. This tumor is notoriously difficult to treat in part because chemotherapy drugs injected on their own often are unable to cross the blood-brain barrier, which is the system of protective blood vessels that surround the brain. Also, most drugs do not stay concentrated in the tumor tissue long enough to be effective.
The drug doxorubicin (DOX) is a common chemotherapy agent that is a promising treatment for a broad range of cancers, and served as a model drug for treatment of brain tumors when injected directly into the tumor. Ho’s team originally developed a strategy for strongly attaching DOX molecules to ND surfaces, creating a combined substance called ND-DOX.
Nanodiamonds can carry a broad range of drug compounds and prevent the ejection of drug molecules that are injected on their own by proteins found in cancer cells. Thus the ND-DOX stays in the tumor longer than DOX alone, exposing the tumor cells to the drug much longer without affecting the tissue surrounding the tumor.
Ho and colleagues hypothesized that glioblastoma might be efficiently treated with a nanodiamond-modified drug using a technique called convection enhanced delivery (CED), by which they injected ND-DOX directly into brain tumors in rodent models.
The researchers found that the ND-DOX levels in the tumor were retained for a duration far beyond that of DOX alone. The DOX was taken into the tumor and stayed in the tumor longer when attached to NDs. ND-DOX also increased programmed cell death (apoptosis) and decreased cell viability in glioma (brain cancer) cell lines.
Their results also showed for the first time that ND- DOX delivery limited the amount of DOX that was distributed outside the tumor and reduced toxic side effects while keeping the drug in the tumor longer and increasing tumor-killing efficiency for brain cancer treatment. Treatment was more effective and survival time increased significantly in rats treated with ND-DOX compared to those given unmodified DOX. Further research will expand the list of brain cancer chemotherapy drugs that can be attached to the ND surface to improve treatment and reduce side effects.
“Nanomaterials are promising vehicles for treating different types of cancer,” Ho said, “We’re looking for the drugs and situations where nanotechnology actually helps chemotherapy function better, making it easier on the patient and harder on the cancer.” Ho adds that a project of this scale has been successful due to the multi-disciplinary and proactive interactions between his team of bioengineers and outstanding clinical collaborators from Northwestern and Lurie Children’s Hospital.
Ho went on to say that the ND has many facets, almost like the surface of a soccer ball, and can bind to DOX very strongly and quickly. To have a nanoparticle that has translational significance it has to have as many benefits as possible engineered into one system as simply as possible. CED of ND-DOX offers a powerful treatment delivery system against these very difficult and deadly brain tumors.
The study appears in the advance online issue of the peer-reviewed journal Nanomedicine: Nanotechnology, Biology and Medicine.
(Source: newswise.com)
Robots Could One Day Help Surgeons Remove Hard to Reach Brain Tumors
NIBIB-funded scientists and engineers are teaming up with neurosurgeons to develop technologies that enable less invasive, image-guided removal of hard-to-reach brain tumors. Their technologies combine novel imaging techniques that allow surgeons to see deep within the brain during surgery with robotic systems that enhance the precision of tissue removal.
A robot that worms its way in
The median survival rate for patients with glioblastomas, or high grade primary brain cancer, is less than two years. One factor contributing to this low rate is the fact that many deep-seated and pervasive tumors are not entirely accessible or even visible when using current neurosurgical tools and imaging techniques.
But several years ago, J. Marc Simard, M.D., a professor of neurosurgery at the University of Maryland School of Medicine in Baltimore (UMB), had an insight that he hoped might address this problem. At the time, he had been watching a TV show in which plastic surgeons were using sterile maggots to remove damaged or dead tissue from a patient.
“Here you had a natural system that recognized bad from good and good from bad,” said Simard. “In other words, the maggots removed all the bad stuff and left all the good stuff alone and they’re really small. I thought, if you had something equivalent to that to remove a brain tumor that would be an absolute home run.”
Image: Initial prototype for the minimally invasive neurosurgical intracranial robot. Image courtesy of University of Maryland.
And so Simard teamed up with Rao Gullapalli, Ph.D., professor of diagnostic radiology and nuclear medicine also at UMB, as well as Jaydev Desai, Ph.D., professor of mechanical engineering at the University of Maryland, College Park, to develop a small neurosurgical robot that could be used to remove deep-seated brain tumors.
Within four years, the team had designed, constructed, and tested their first prototype, a finger-like device with multiple joints, allowing it to move in many directions. At the tip of the robot is an electrocautery tool, which uses electricity to heat and ultimately destroy tumors, as well as a suction tube for removing debris.
“The idea was to have a device that’s small but that can do all the work a surgeon normally does,” said Simard. “You could place this small robotic device inside a tumor and have it work its way around from within, removing pieces of diseased tissue.”
A key component of the team’s device is its ability to be used while a patient is undergoing MRI. By replacing normal vision with continuously updated MRI, the surgeon is able to visualize deep-seated tumors and monitor the robot’s movement without having to create a large incision in the brain.
In addition to reducing incision size, Simard says the ability to view the brain under continuous MRI also helps surgeons keep track of tumor boundaries throughout an operation. “When we’re operating in a conventional way, we get an MRI on a patient before we do the surgery, and we use landmarks that can either be affixed to the scalp or are part of the skull to know where we are within the patient’s brain. But when the surgeon gets in there and starts to remove the tumor, the tissues shift around so that now the boundaries that were well-established when everything was in place don’t exist anymore, and you’re confronted once again with having to distinguish normal brain from tumor. This is very difficult for a surgeon using direct vision, but with MRI, the ability to discriminate tumor from non-tumor is much more powerful.”
Steve Krosnick, M.D., a program director at NIBIB, says real-time MRI guidance during brain tumor surgery would be a tremendous advantage. “Unlike pre-operative MRI or intermittent MRI, which requires interruption of the surgical procedure, real-time intra-operative MRI offers rapid delineation of normal tissue from tumor while accounting for brain shifts that occur during surgery.”
But designing a neurosurgical device that can be used inside an MRI magnet is no easy task. One of the first issues you have to consider, said Gullapalli, is a surgeon’s access to the brain. “When you scan a person’s brain during an MRI, he’s deep inside the machine’s tunnel. The problem is, how do you get your hands on the brain while the patient’s in the scanner?”
The team’s solution was to give the surgeon robotic control of the device in order to circumvent the need to access the brain directly. In other words, a surgeon can insert the robot into the brain while the patient is outside of the scanner. Then, when the patient moves into the scanner, the surgeon can sit in a different room and –while watching MRI images of the brain on a monitor—move the robot deep inside the brain and direct it to electrocauterize and aspirate the tissue.
Jaydev Desai, the team’s mechanical engineer, says the most challenging aspect of the project has been designing a robot that can be controlled inside the magnetic field of an MRI. While robots are often controlled via electromagnetic motors, this was not an option because, besides being magnetic, these motors create significant image distortion, making it impossible for the surgeon to perform the task. Other potential mechanisms such as hydraulic systems were off the table due to concerns about fluid leakage.
Instead, Desai decided to use shape memory alloy (SMA)—a material that alters its shape in response to changes in temperature—to control the robot’s movement. In the most recent prototype—developed by Desai and his team at the Robotics, Automation, and Medical Systems (RAMS) laboratory at the University of Maryland, College Park—a system of cables, pulleys and SMA springs are used. This cable and pulley system is an improvement from their previous prototype which caused some image distortion.
Image: The newest prototype for the minimally invasive neurosurgical intracranial robot uses a system of pulleys and springs to move the robot. Source: Jaydev Desai, University of Maryland
With continued support from NIBIB, Desai and colleagues are now working to further reduce image distortion and to test the safety and efficacy of their device in swine as well as in human cadavers. Though it will be several years before their device finds its way into the operating room, Simard is excited by the prospect. “Advancing brain surgery to this level where tiny machines or robots could navigate inside people’s heads while being directed by neurosurgeons with the help of MRI imaging…It’s beyond anything that most people dream of.”
Scoping the brain
On the opposite side of the country, a different group of engineers and neurosurgeons is also working to develop an image-guided, robotically-controlled neurosurgical tool. Lead by Eric Seibel, Ph.D., a professor of mechanical engineering at the University of Washington, the team is attempting to adapt a scanning fiber endoscope—a tool initially developed by Seibel to image inside the narrow bile ducts of the liver—so that it can be used to visualize the brain during surgery.
An endoscope is a thin, tube-like instrument with a video camera attached to its end that can be inserted through a small incision or natural opening in the body to produce real-time video during surgery. Endoscopes are an essential component of minimally invasive surgeries because they allow surgeons to view the inside of the body on a monitor without having to make a large incision.
However, there are many parts of the body such as small vessels and ducts as well as areas deep in the brain that are inaccessible to conventional endoscopes. Although ultrathin endoscopes have recently been developed, Seibel says these smaller scopes come with the price of greatly reduced image resolution.
“Right now, with the current state of the art ultrathin endoscopes, I calculate based on the field of view and their resolution that the person looking at that display would see so little as to be classified in the US as legally blind,” said Seibel.
Image: Microfabricated optical fiber scanner emitting red laser light, with scan amplitude of 1 mm peak-to-peak. Image courtesy of Eric Seibel, University of Washington
But with support from NIBIB over ten years ago, Seibel began working on a new type of endoscope that could fit into tiny crevices in the body while retaining high image quality. His end product was a new type of endoscope that, despite having the diameter of a toothpick, can provide doctors with microscopic views of the inside of the body.
Seibel retained image quality while significantly reducing the size of his scope by eschewing traditional endoscope models. Instead of a light source and a video camera, Seibel’s scope consists of a single optical fiber—approximately the size of a human hair—located in the middle of the scope. The fiber releases white laser light (a combination of green, red, and blue lasers) when vibrated at a particular frequency. By directing the laser light through a series of lenses in the scope, it can be reflected widely within the body, providing a 100 degree field of view. As the white laser light interacts with tissue, it picks up coloration and scatters it back to a ring of additional optical fibers which transmit this information to a monitor.
“It’s almost like putting your eyes inside the body so you can see with the wide field view of your human vision,” said Seibel.
In collaboration with three neurosurgeons and an electrical engineer, Seibel is now working to secure his novel endoscope to the tip of a robotically controlled micro-dissection neurosurgical tool.
As opposed to larger traditional endoscopes, Seibel say his scanning fiber endoscope is barely noticeable.
“It’ s like a piece of wet spaghetti,” said Seibel. “It’s even smaller then a piece of wet spaghetti in diameter, but it feels like that. So when it is actually at the tip of the surgeon’s tool, the surgeon wouldn’t feel it dragging behind her.”
One advantage of having the endoscope under robotic control is that the brain can be imaged at a higher magnification.
“A surgeon couldn’t hold a microscope steady in her hand while performing surgery, but the robot can,” said Seibel.
Microscopic detail is essential when trying to determine the border between healthy tissue—which if removed could lead to neurological deficits—and cancerous tissue—which if left in the brain could allow a tumor to return.
Krosnick says he’s excited by the combination of high-quality imaging and robotic enabled micro-neurosurgery. “It addresses a critical need, which is to discern tumor margins at high resolution while minimizing disruption to normal structures.”
Seibel believes this discrimination between cancerous and healthy tissue could be enhanced even further by taking advantage of the fact that his scanning endoscope is also able to detect fluorescence. One of the main focuses of his current research is a collaboration with Jim Olson, M.D., Ph.D. at the Fred Hutchinson Cancer Research Center, who is the inventor of a substance called “tumor paint”.
Tumor paint is a fluorescent probe that attaches to cancerous but not healthy cells when injected into the body. Seibel says the ultimate goal would be to give a patient an injection of tumor paint and then use his endoscope to create an image of the fluorescing cancer cells as well as a colored anatomic image of the brain. The two images could then be merged on a screen for the surgeon to view during an operation.“You would be able to see all the structure that a surgeon would see, but you’d also see those molecular pinpoints of light that are cancer cells…and from there the robot can be used to resect, or remove, these small cells of cancer, and it can do it very precisely because you don’t have the shaking of a human holding it.”
Image: Tumor paint is made of a compound extracted from scorpion venom that can travel through the blood brain barrier and bind specifically to tumor cells. Source: iStockphoto
Seibel concluded by saying, “There’s a real niche for video-quality, high-resolution, multi-modal imaging that’s in a tiny package so that it can be put on microscopic tools for minimally invasive medicine. I really feel it’s an enabling technology that could move the whole field forward.”
Krosnick is enthusiastic about the progress the two teams have made so far. “These are innovative technologies that, if effective, could significantly add to the brain surgery armamentarium. They’re still early in development, but I think both show considerable promise.” He concluded by emphasizing that, like all new devices, these technologies would need to undergo a series of clinical trials to ensure that they are safe and effective before making their way into an operating room.
(Source: nibib.nih.gov)
New laser-based tool could dramatically improve the accuracy of brain tumor surgery
Imaging technique tells tumor tissue from normal tissue, could be used in operating room for real-time guidance of surgery
A new laser-based technology may make brain tumor surgery much more accurate, allowing surgeons to tell cancer tissue from normal brain at the microscopic level while they are operating, and avoid leaving behind cells that could spawn a new tumor.
This image of a human glioblastoma brain tumor in the brain of a mouse was made with stimulated Raman scattering, or SRS, microscopy. The technique allows the tumor (blue) to be easily distinguished from normal tissue (green) based on faint signals emitted by tissue with different cellular structures.
In a new paper, featured on the cover of the journal Science Translational Medicine, a team of University of Michigan Medical School and Harvard University researchers describes how the technique allows them to “see” the tiniest areas of tumor cells in brain tissue.
They used this technique to distinguish tumor from healthy tissue in the brains of living mice — and then showed that the same was possible in tissue removed from a patient with glioblastoma multiforme, one of the most deadly brain tumors.
Now, the team is working to develop the approach, called SRS microscopy, for use during an operation to guide them in removing tissue, and test it in a clinical trial at U-M. The work was funded by the National Institutes of Health.
A need for improvement in tumor removal
On average, patients diagnosed with glioblastoma multiforme live only 18 months after diagnosis. Surgery is one of the most effective treatments for such tumors, but less than a quarter of patients’ operations achieve the best possible results, according to a study published last fall in the Journal of Neurosurgery.
“Though brain tumor surgery has advanced in many ways, survival for many patients is still poor, in part because surgeons can’t be sure that they’ve removed all tumor tissue before the operation is over,” says co-lead author Daniel Orringer, M.D., a lecturer in the U-M Department of Neurosurgery who has worked with the Harvard team since a chance meeting with a team member during his U-M residency.
On the left, the view of the brain that neurosurgeons currently see during an operation using bright-field microscopy. On the right, an SRS microscopy view of the same area of brain - in this case, a mouse brain that has had human brain tumor tissue transplanted into it. SRS might someday allow surgeons to see this same view of patients’ brains.
“We need better tools for visualizing tumor during surgery, and SRS microscopy is highly promising,” he continues. “With SRS we can see something that’s invisible through conventional surgical microscopy.”
The SRS in the technique’s name stands for stimulated Raman scattering. Named for C.V. Raman, one of the Indian scientists who co-discovered the effect and shared a 1930 Nobel Prize in physics for it, Raman scattering involves allows researchers to measure the unique chemical signature of materials.
In the SRS technique, they can detect a weak light signal that comes out of a material after it’s hit with light from a non-invasive laser. By carefully analyzing the spectrum of colors in the light signal, the researchers can tell a lot about the chemical makeup of the sample.
Over the past 15 years, Sunney Xie, Ph.D., of the Department of Chemistry and Chemical Biology at Harvard University – the senior author of the new paper — has advanced the technique for high-speed chemical imaging. By amplifying the weak Raman signal by more than 10,000 times, it is now possible to make multicolor SRS images of living tissue or other materials. The team can even make 30 new images every second — the rate needed to create videos of the tissue in real time.
Seeing the brain’s microscopic architecture
A multidisciplinary team of chemists, neurosurgeons, pathologists and others worked to develop and test the tool. The new paper is the first time SRS microscopy has been used in a living organism to see the “margin” of a tumor – the boundary area where tumor cells infiltrate among normal cells. That’s the hardest area for a surgeon to operate – especially when a tumor has invaded a region with an important function.
As the images in the paper show, the technique can distinguish brain tumor from normal tissue with remarkable accuracy, by detecting the difference between the signal given off by the dense cellular structure of tumor tissue, and the normal healthy grey and white matter.
The authors suggest that SRS microscopy may be as accurate for detecting tumor as the approach currently used in brain tumor diagnosis – called H&E staining.
This image shows the same areas of brain, imaged with SRS microscopy (left) and conventional H&E staining, which is the current technique used to diagnose brain tumors at the tissue level. The research suggests that SRS microscopy could be as accurate as H&E staining in allowing doctors to see tumors - without having to remove tissue or inject dyes into the patient.
The paper contains data from a test that pitted H&E staining directly against SRS microscopy. Three surgical pathologists, trained in studying brain tissue and spotting tumor cells, had nearly the same level of accuracy no matter which images they studied. But unlike H&E staining, SRS microscopy can be done in real time, and without dyeing, removing or processing the tissue.
Next steps: A smaller laser, a clinical trial
The current SRS microscopy system is not yet small or stable enough to use in an operating room. The team is collaborating with a start-up company formed by members of Xie’s group, called Invenio Imaging Inc., which is developing a laser to perform SRS through inexpensive fiber-optic components. The team is also working with AdvancedMEMS Inc. to reduce the size of the probe that makes the images possible.
A validation study, to examine tissue removed from consenting U-M brain tumor patients, may begin as soon as next year.
(Source: uofmhealth.org)