Category Archives: Research Projects

The Role of MicroRNAs Monocyte-Mediated Glioma Pathogenesis

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Galina Gabriely, PhD

Glioblastoma is the most aggressive form of brain cancer, affecting mainly people of middle age. Current available therapies include surgery and radiotherapy, which is usually given in combination with chemotherapy. Despite these aggressive interventions and extensive knowledge about biology of tumor cells, glioblastoma remains incurable. Interestingly, malignant glioblastoma is highly populated by immune cells, called monocytes. These cells are recruited from the blood and enter glioblastoma in order to eradicate cancer. However, once they reach the brain tumor, monocytes change under the influence of malignant environment, and become unable to eliminate tumor cells. Instead, they support glioblastoma growth by clearing the way for cancer spread in the brain.

Dr. Gabriely’s project proposes to reprogram the monocytes and restore their intrinsic ability to destroy abnormal tumor cells. Her team will use microRNAs—recently discovered master genes—to activate monocytes. Initially, to identify potential microRNA targets, the team will compare their content between normal blood monocytes and glioma-associated monocytes. Then, therapeutic microRNAs will be identified by using a screen system of co-culturing monocytes with glioma cells. Finally, they will validate the therapeutic properties of microRNA modulation in monocytes invading glioma cells in an established mouse glioma model.

Our pioneering approach hold promise to rescue glioblastoma patients by developing a novel previously unexplored way to treat this devastating brain malignancy. Moreover, it will provide the fundamental scientific information about immune cells populating glioma for comprehensive understanding of glioma biology necessary for development of targeted treatments.

Elucidation and Small Molecule Inhibition of Slug-induced Invasion and Metastases in Glioblastoma and Other Cancers

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Dr. Mark Johnson is an established member of the Department of Neurosurgery at Brigham & Women’s Hospital and an expert on brain tumors. He has already accomplished several highly original investigations into the causes of glioblastoma. In this grant he is studying “transcription factors”—signaling proteins within the cell that turn both genes and proteins on and off and contribute to cancer growth. Specifically, Dr. Johnson has identified the cell regulator SNAI2/Slug (called “slug” by people in the field) that is highly expressed in glioblastomas and has strong circumstantial evidence of participation in continued growth of the tumor.

One exciting element related to this project is that slug-induced invasion can be inhibited by small molecule inhibitors, some of which are currently in clinical trials for other applications. This is an entirely new strategy to decrease the invasion of glioblastoma to adjacent parts of the brain and is likely to have implications for other tumors and metastases.

Dr. Johnson’s work will be done with mouse models of glioblastoma, metastatic melanoma, and metastatic breast cancer. In addition, the proposal will study the way in which glioblastoma cells migrate in a special laboratory dish, observing the effects of the small molecule inhibitors on this migration.

This is focused work on the pathways of brain tumor development never investigated before and has the potential to be developed into a new series of drugs for brain tumors.

Analysis of microRNA Determinants of Survival in Glioblastoma

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Anna Krichevsky, PhD

Glioblastoma (GBM) is the most common and aggressive type of brain malignancy in adults and also accounts for approximately 10% of pediatric central nervous system tumors. The average lifespan of GBM patients is less than one year even with therapeutic interventions and has only minimally improved over the past 25 years. Therefore, there is a critical need for new molecular targets, concepts, and approaches to treat this devastating disease.

The discovery of microRNAs, small regulatory molecules with a great potential to control gene expression, has revolutionized the field of cancer biology. It suggested an entirely new layer of gene regulation that might be involved in progression and maintenance of human cancer. A single microRNA can directly regulate multiple target genes, and thereby control expression of multiple proteins involved in diverse signaling pathways. Over the past seven years, Dr. Krichevsky and her team have focused on microRNAs involved in glioma initiation and progression, and today have mounting evidence indicating that GBM growth and invasiveness are closely regulated by microRNAs.

The team has identified and investigated three specific onco-microRNAs—miR-21, miR-10b, and miR-296—as potent regulators of glioma cell division, tumor resistance to death signals, and glioma-induced angiogenesis. These molecules drive GBM growth. More recently, they predicted several protective microRNAs that may slow-down tumor growth and thus significantly increase patients’ survival. This studies the effects of such molecules on glioma growth in cultured cells and animal models of human GBM. If successful, it may lead to the development of novel microRNA-based therapies for gliomas.

Novel Use of Neural Stem Cells for the Targeted Treatment of Spinal Cord Gliomas

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Alexander E. Ropper, MD

The incidence of primary spinal cord tumors has increased in recent decades. While more common in the brain, tumors also occur in the spinal cord. A variety of types are seen such as astrocytomas, glioblastomas, and ependymomas. While surgery can be effective, patients may be left with paralysis or sensory loss due to the sensitivity of the surrounding tissue that must be dissected. Patients with these tumors may die from worsening spinal cord spread or from infections related to their debilitated condition.

Alternative approaches to the treatment of brain gliomas have received significant attention and this project intends to modify one of these approaches for use in the spinal cord. A novel treatment is the use of neural stem cells (NSCs) to track and kill tumor cells. Neural stem cells have a unique ability to seek, follow, and contact tumor cells in the nervous system, even when the stem cells are administered intravenously. This tumor-cell oriented behavior of stem cells is triggered by molecules that are secreted by tumors during their growth.

Previous work by collaborators of Dr. Ropper has demonstrated that neural stem cells can be genetically engineered to carry a chemical to tumors. Dr. Ropper’s team intends to insert cytosine deaminase into neural stem cells. This enzyme converts the non-toxic compound [5-fluorocytosine (5-FC)] into a potent cancer chemotherapy, (5-fluorouracil, or 5-FU). By utilizing the inherent migratory nature of NSCs to target tumor cells throughout the spinal cord, the team hopes to selectively deliver the toxic chemotherapy only to the tumor, sparing normal spinal cord tissue.

To test this hypothesis, the team will first develop a unique animal tumor model by injecting glioma cells into the spinal cord of rats. Then they will give intravenous or intraspinal genetically engineered stem cells, followed by intravenous injection of the non-toxic precursor containing 5-FC. The team expects the toxic 5-FU chemotherapy compound to be produced only in the immediate vicinity of tumor cells. This would constitute the first multidisciplinary approach to tackle the disease of spinal cord malignant tumors and lead to a better overall prognosis in patients with aggressive malignancies in the spinal cord.

Investigating Meningioma Recurrence with the Comprehensive Resources of the Nurses’ Health Study

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Although most meningiomas are classified as benign, substantial growth of these tumors can cause major neurological damage and cause substantial disability.

Ionizing radiation and hereditary syndromes are established risk factors for meningioma, and while hormone treatments have been classified as an established risk factor, data are sparse and inconsistent. Moreover, few prognostic markers exist to guide decision making for the management of meningioma patients.

Our understanding of why meningiomas occur and the likely outcomes (such as tumors recurring after the original surgery) could be greatly enhanced by establishing a comprehensive resource linking clinical information with tumor samples. The Nurses’ Health Study (NHS) provides a unique opportunity. The first cohort was initiated in 1976 at the Channing Lab at Brigham and Women’s Hospital with the enrollment of 121,700 female, U.S.-registered nurses between the ages of 30 and 55. This became known as NHS I. This cohort has been followed carefully now for 35 years and detailed information has accrued on factors relevant to women’s health, exposure information and meningioma incidence and outcome. In 1989, an additional 116,678 women aged 25–42 were enrolled in the NHS II. The prospective accumulation of information and the length of follow-up are fundamental advantages of these cohorts.

Dr. Santagata’s project will examine both Nurses’ studies for insights into meningiomas—both causes and outcomes. More than 600 participants in the two studies reported being diagnosed with meningioma, providing a wealth of information to review. Tissue from these cases, however, has not been collected. Along with Dominique Michaud at Brown University, Dr. Santagata’s team will build a tissue resource from the NHS meningioma samples that could provide vast opportunities for epidemiologic and biomarker studies.

On-Chip Characterization of Brain Tumor Heterogeneity by Single Cell Mass Spectrometry

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Despite the arsenal of developed and FDA-approved anti-cancer drugs, cancer is still a leading cause of death. The limiting factor in treating cancers is no longer solely drug availability, but now also includes the need for more comprehensive diagnostic approaches. Biochemical factors that cause tumors to develop and progress vary from one cancer to another, as well as from one patient to another. Personalized cancer care requires treatment that specifically targets biomolecules defining a given tumor, based on knowledge of the tumor’s molecular features.

The World Health Organization recognizes more than 125 types of brain tumors. Glial tumors account for 40% of all intracranial tumors. The most malignant form, glioblastoma multiforme (GBM) still resists elaborate treatment with a median survival of 12–15 months. Nevertheless, there is wide variation in survival with some patients responding well to treatment while others do not. In order to extend survival and improve quality of life for patients with GBM, it is necessary to choose the most effective treatment. Characterizing the individual molecular characteristics of a patient’s tumor can inform treatment selection and optimize outcomes.

Unfortunately, brain tumors are heterogeneous and consist of populations of cells with different degrees of tumor initiating potential, and different susceptibility to treatment. The isolation and characterization of tumor stem cells in samples of human brain tumor tissue have been limited in terms of clinical translation due to the intensive labor involved in each specimen analysis.

The project team proposed an approach that uses microfabricated devices for single cell culture and analysis of brain tumor cells. The technology could help identify and implement clinical markers that correlate with the effectiveness of a treatment. This project will leverage the collaborative expertise of three groups in the areas of mass spectrometry and neuroscience (Nathalie Agar, BWH, principal investigator), genetics and computational biology (Philip De Jager, MD, BWH, co-principal investigator), and single-cell bioanalytical engineering (Christopher Love, PhD, MIT, co-principal investigator).

Reconstructing the Meningioma Genome

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Meningiomas are the most common brain tumor. Although they are typically cured by surgery, up to 20% recur. Moreover, surgery is often difficult to perform depending on where in the skull the meningioma arises. Therefore, we need additional treatment options. Unfortunately, we do not have good medications to treat these tumors. Like other cancers, meningiomas arise as a result of successive mutations in their DNA. As a cell divides, it must make copies of its DNA for its daughter cells. Mutations represent mistakes in this copying process. If these mutations disrupt the internal controls of a meningioma precursor cell, leading it to grow in an uncontrolled and inexorable manner, it will develop into a meningioma.

One way to develop effective treatments for meningioma is to identify the mutations that led to those cancers and figure out their implications. This method has worked for certain types of leukemia, lung cancer, melanoma, and other cancer types, in part by accomplishing two goals. First, by determining how these mutations disrupt the internal controls of meningioma cells, we can fashion new treatments that reverse the mutations’ disruptive effects. Second, by understanding which mutations an individual meningioma has, we may be able to predict how it will behave. For instance, we may be able to identify those 20% of patients whose meningiomas are likely to recur, and give them additional treatment up front to minimize this likelihood.

The mutations that lead to meningioma can occur anywhere in the genome. In principle, the only way to detect  these mutations is to reconstruct the entire genome of a meningioma and compare it to the normal genome of the same patient. Until recently, this has been prohibitively expensive—indeed, The Human Genome Project cost $3 billion and reconstructed only a single human genome. Moreover, to identify the important mutations in meningioma, we must reconstruct many meningiomas and normal genomes and identify the mutations that recur most often. Fortunately, recent technical advances have led to plummeting sequencing costs, making it possible to reconstruct entire cancer and normal genomes at reasonable cost. We have been involved in national and international efforts to reconstruct the genomes of several cancer types. We have also developed the analytic methods to detect the differences between cancer genomes and normal genomes and determine which of these differences are important.

In this project, we will perform similar analyses in meningioma, to comprehensively assess the genomes of four meningiomas and their normal counterparts, and identify all the mutations that led to these meningiomas. We anticipate that this knowledge will lead to a fundamental understanding of how meningiomas arise and will enable the development of targeted treatments that reverse the effects of the mutations that lead to meningioma.

Co-local Delivery of Chemotherapeutics and Parp-inhibitors (Glioma Sensitizers) to Treat Glioblastoma Multiforme

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Glioblastoma (GBM) is one of the most aggressive and treatment-resistant of all human cancers. The median survival for these patients remains only 9–15 months from the time of diagnosis. A major limitation to effective treatment for GBM is the inability of treatments to cross the blood-brain/blood-tumor barrier, and the presence of drug efflux pumps, which prevent adequate concentrations of drugs to be achieved at the tumor. Many potential treatments fail due to i) their inability to target cancer cells that have invaded deep into normal brain tissue; ii) their inability to achieve drug concentrations required to kill cancer cells in the brain; or iii) limited toxicity of existing chemotherapy drugs against resistant glioma cells.

To overcome these major limitations, Jeffrey Karp, MD, and. Lata Menon, MD, will work together to use a new treatment approach that includes delivering tumor cell sensitizers and chemotherapy drugs at the same time. They aim to develop a new approach that will serve as a paradigm shift in the treatment of the GBM. This collaborative project takes advantage of the capability and resources at Harvard Medical School, Brigham and Women’s Hospital, and Massachusetts Institute of Technology.

Recently, Dr. Karp’s lab team has designed a new way to synthesize drug-based gels that can easily be injected into cancer cells and can accommodate high drug concentrations that will ensure that every molecule in the gel contains drug. The drug-based gels can accommodate multiple drugs for combination therapy, can be designed to remain stable for months in healthy brain tissue, and can be delivered in the event of tumor growth or recurrence.

Dr Menon will study the fate, delivery, and the treatment efficacy of the drug based gel in subcutaneous and orthotopic models of human glioma. This research will help prove how this gel works in animal models, so that this approach can be used to treat aggressive brain tumors.

Identifying Transcription Factor Targets in Meningioma: A Non-Oncogene Approach

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Dr. Sandro Santagata is a neuropathologist focused on discovering new diagnostic markers for meningioma as well as identifying new molecular targets for cancer treatment. His research involves collaboration with the BWH Pathology Department, the Whitehead Institute, and the Broad Institute.

A central focus in developing modern cancer treatments is the goal of targeting specific components of pathways that are aberrantly activated through mutations or changing positions. Despite the dependence of cancer cells on such pathways, the survival of these cells is also critically dependent upon non-mutated, non-oncogene systems that serve fundamental roles in cell survival. These non-oncogene targets offer different treatment options aimed at common and unusual biological requirement of cancer cells rather than at individual oncogeni lesions. Dr. Santagata’s team is working to identify fundamental non-oncgene targets of meningioma. These factors will help gain insight into the biology of meningioma formation and proliferation, will serve as useful diagnostic markers, and may shed light on new mechanisms for developing treatments.

A number of studies have used gene expression profiling to investigate the biology of meningiomas with a particular focus on identifying markers and mediators of tumor progression. Identification of transcription factors, however, strikingly has been overlooked. Meningioma transcription factors could serve as both excellent diagnostic tools in addition to sensitive targets for treatment intervention. Dr. Santagata team’s goal is to identify the transcription factors that are central to the core transcriptional identity of meningothelial cells and meningioma, which would provide both important diagnostic tools and new insights into innovative approaches for selective treatments for meningioma.

In Vivo Efficacy of MEMs Systems-Driven Intracranial Delivery of Temozolomide in the Treatment of High Grade Glioma

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Glioblastoma multiforme (GBM) remains the most common and aggressive form of primary brain tumors. Despite improvements in neurosurgical technique, neuroimaging, and radiation, the prognosis associated with these tumors remains grim. There is an important role for improvements in chemotherapy, particularly to prevent recurrence. Given that a majority of malignant gliomas recur within two centimeters of the original lesion, local delivery of chemotherapies may prove effective in reducing the risk of tumor recurrence. Delivery of chemotherapy to the GBM tumor bed has the demonstrable ability to diffuse throughout surrounding tissue. This ability is particularly attractive for infiltrative tumors, such as GBM, where tumor cells penetrate normal neural tissue.

Data from animal experiments demonstrate that a higher concentration of chemotherapy can be achieved in the brain with local delivery compared to IV injection. Until recently, efforts in local drug delivery focused on a constant rate of drug release though this may not be the ideal method of drug delivery for all tumors. The use of microchip-driven drug delivery provides the potential for on-demand and variable chemotherapy delivery to the tumor bed, that is, the most likely site of tumor recurrence. Such a system, adapted to contain several drug reservoirs, could facilitate the release of different chemotherapeutic agents over time; in turn, multi-drug treatment may mitigate chemotherapeutic-resistance seen in vivo work from several groups has supported the notion that variable drug release has improved effectiveness against glioma cell lines.

A microelectromechanical systems (MEMS) reservoir-based device has been designed by an injection-molding technique that allows for the delivery of chemotherapy on-demand. One can envision MEMS as a uniquely powerful platform in the future for delivering potent therapeutic agents whose temporal administration is vital to their efficacy, and whose effects are naturally amplified by the human body. Demonstrating that such devices have improved efficacy against a rodent glioma model would represent a departure from prior work on drug-delivery, as those efforts focused largely on achieving constant release profiles. Tunable, on-demand, pulsatile drug release from locally-implantable devices will hopefully show promise in the treatment of high-grade gliomas and may lead to the first advance in chemotherapeutic delivery for brain tumors in over one decade.

A Pilot Trial of Cytosine Deaninase-Expressing Mesenchymal Stromal Cells in Glioblastoma Therapy

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drpeterblack

Peter Black, MD, PhD

Boston Children’s Hospital, Brigham and Women’sHospital, Harvard Medical School, Dana-Farber Institute

Glioblastoma (GBM) is among the most aggressive and treatment-resistant of all human cancers, with a typical life expectancy of 9–15 months after diagnosis. A new therapeutic strategy, developed by Dr. Peter Black and his multidisciplinary team at BWH, aims to provide new hope to patients diagnosed with this primary brain tumor.Dr. Black’s groundbreaking clinical trial uses a specific type of the body’s own bone marrow cells, genetically modified, to directly target and destroy the tumor cells and significantly reduce their growth. This clinical trial will soon accept adult patients and holds great promise for expanding the use of gene therapy in brain cancer treatment.

Familial Study of Meningioma

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Elizabeth Claus, MD, PhD, Brigham and Women’s Hospital, Yale University

With BSF funding in 2010, Dr. Claus and her research team will continue to approach and collect 1) interview data and 2) biological specimens in the form of blood/buccal/saliva as well as paraffin-embedded tumor blocks from families with multiple members diagnosed with meningioma.

The overall goal of this seed funding is to enable Dr. Claus to collect pilot data critical to her pursuit of a larger federal grant for DNA testing for a formal genetic linkage analysis of meningioma. Environmental exposure data will also be collected during this study.

Comprehensive Identification of Therapeutic Targets in Meningioma

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Ian Dunn, MD

Prior BSF funding allowed Dr. Dunn to study the function of kinases in meningioma; since that time, Dr. Dunn has developed methods to study over 10,000 genes (including the close to 600 kinase genes) more efficiently and more cheaply and secure data derived from genome-scale RNA-interference (RNAi) screening.

Prior BSF funding allowed Dr. Dunn to study the function of kinases in meningioma; since that time, Dr. Dunn has developed methods to study over 10,000 genes (including the close to 600 kinase genes) more efficiently and more cheaply and secure data derived from genome-scale RNA-interference (RNAi) screening.

An important aspect of Dr. Dunn’s project in 2010 is that, unlike prior projects, it entails additional methods of identifying cancer-causing genes in meningioma, largely due to new collaborations developed within the Broad Institute.  In addition to functional genomics and RNAi screening—Dr. Dunn and his team will also study gene expression, global DNA amplifications/deletions, and mutation analysis.  Taken together, these approaches will permit the combination of functional approaches via RNA-interference and structural genetic changes.  Dr. Dunn has identified oncogenes in other cancer types using this approach.

The combination of several genomic approaches represents a large effort in the lab to identify oncogenes using integrated genomics; the lab is undertaking a large effort to functionally and structurally profile hundreds of cancer cell lines in a collaborative effort with several other well-established laboratories, each of which is contributing cell lines to the collaboration. In part because of funding provided by the BSF, meningioma cell lines developed by Dr. Dunn were selected as the first of over 300 cell lines from numerous laboratories to be studied.  Dr. Dunn is confident that this combinatorial approach will shed new light on the genetics of meningioma.

The Role of the cdc20-Anaphase Promoting Complex Signaling Pathway in Cerebellar Granule Cell Precursor Development and Medulloblastoma Migration

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Dr. Albert Kim, MD, PhD
*Funded in collaboration with the Daniel E. Ponton Fund for the Neurosciences at Brigham and Women’s Hospital

Primary brain tumors are the most common solid tumors in children. Among these tumors, medulloblastoma is the most commonly diagnosed, with a startlingly low five-year survival rate, despite current treatments. In order to give these young patients a brighter future, Dr. Albert Kim is studying the role of a specific central nervous system cell in the mechanisms leading to the development of medulloblastoma.

By better understanding the inner workings of these cells, Dr. Kim hopes to create precisely targeted treatments that will stop the tumor growth at its source, and give children a leg up in the fight against brain cancer.

Semi-Automatic Identification of Neurosurgically Important White Matter Tracts Using fMRi + DTT Atlas

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Dr. Golby has special clinical interests in epilepsy and brain tumors, and her research at the Golby Lab focuses on functional brain mapping using both structural and functional imaging techniques to guide neurosurgical planning and intra-operative decision making. BSF funding in 2010 will continue Dr. Golby’s work in integrating information acquired from pre-operative brain mapping with intra-operative brain mapping and intra-operative imaging, to define functional brain anatomy for surgical planning. The goal is to provide the surgeon with optimal information to perform less invasive, safer, and more effective interventions.  This allows patients with lesions in critical brain areas to have optimal surgical treatment with preservation of neurological function.

The Golby Lab originated through funding from the Brain Science Foundation, The Brigham Institute for the Neurosciences, and the National Institutes of Health, allowing Dr. Golby to assemble a team of extraordinary scientists from different backgrounds working collaboratively to advance the field of image-guided surgery and functional brain imaging. By developing brain mapping techniques to better understand the functional anatomy of the brain and applying these techniques to surgical planning and in the operating room, Dr. Golby and her team are ensuring healthier outcomes and improving the quality of life for patients of with brain tumors and epilepsy.

DNA Repair Mechanisms as Targets for Therapy of Pituitary Adenomas

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TMZ is the first new drug of the past 30 years that aggressively and effectively treats malignant gliomas and improves the quality of life for patients. Dr. Edward Laws, seeing the tremendous potential of this treatment, has embarked on a study investigating the use of TMZ on aggressive and malignant pituitary tumors when standard therapies fail.

Promising results are already being reported, and Dr. Laws hopes that this novel approach will pave the way for similar investigations into other types of primary brain tumors.

Mechanisms Underlying Tumor- Associated Seizures

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Suzanne Goh, MD candidate Harvard Medical School Medical Advisor; Dr. Peter McLaren Black, Neurosurgeon in Chief, Brigham and Women’s Hospital

Executive Summary

Individuals with brain tumors frequently have seizures, and the seizures can be as difficult to manage as the brain tumor itself. The onset of seizures in someone who has never had a seizure before can be the first sign of a brain tumor. For others, seizures may not begin until after their brain tumor has been removed.Because seizures themselves can be life threatening, it is critical that patients and physicians discuss the causes and treatments of tumor-associated seizures.

This paper explores the current state of research on tumor-associated seizures. Although a great deal of research has been done, our understanding of the mechanisms underlying these types of seizures is incomplete. We do know that seizures can accompany other types of injury to the brain as well, such as stroke, trauma, infection, neurodegenerative disease, neurosurgery, and other disorders affecting the brain. It is likely that all of these different disorders set the stage for seizure activity by in some way increasing the excitability of neurons.

Overview of Research on Tumor-Associated Seizures

Tumor-associated seizures can occur with all types of brain tumors, but they are more common with some types of brain tumors than with others1:

Frequency of seizures in people with specific types of brain tumors

Ganglioglioma – 90%
Low-grade glioma – 60-85%
High-grade glioma – 54-69%
Glioblastoma – 29-49%
Meningioma – 29-41%
Metastases to the brain – 35%

Some of these types of brain tumors, such as meningiomas, compress adjacent brain tissue but do not invade the normal tissue. Cells of other brain tumors, such as glioblastoma, infiltrate normal brain tissue. Despite differences in behavior, all brain tumors are capable of causing seizures. In order to understand why tumors cause seizures, we must first understand what happens in the brain during a seizure.

Seizure Origin

The brain is comprised of different cell types. The cells in the brain that are responsible for generating and propagating electrical activity are called neurons. The connections between neurons are called synapses. The term “seizure focus” is often used to refer to a cluster of neurons that show increased electrical activity. The increased electrical activity of the neurons in a seizure focus can be due to a number of factors: altered properties of the neurons, altered synaptic connections between neurons, or altered conditions surrounding the neurons in their extracellular environment. Tumors, blood clots, scar tissue, and brain malformations are all known to alter these factors. The neurons within a seizure focus differ in behavior from most neurons in that they are capable of exhibiting a repetitive and synchronized electrical response known as a paroxysmal depolarizing shift. This is a sudden, large change in electrical charge that lasts a fraction of a second. If the abnormal electrical activity remains confined to the seizure focus, a seizure will not occur, but if the abnormal electrical activity spreads beyond the seizure focus, a seizure may occur.

Tumor-associated Seizures

In individuals with brain tumors, where is the seizure focus? It is logical to assume that the seizure focus is in the tumor itself. Since a brain tumor is a collection of abnormal cells, they might be prone to generate abnormal electrical activity. Indeed, tumor cells taken directly from certain types of brain tumors (namely gangliogliomas and dysembryoplastic neuroepithelial tumors) have shown the ability to generate electrical activity.2 This has led some researchers to hypothesize that hyperexcitability may be an intrinsic feature of certain types of tumor cells.

There is also evidence, however, that seizures in the setting of a brain tumor may be due to alterations in the brain tissue surrounding the tumor, rather than within the tumor. The fact that seizures commonly persist despite removal of the tumor mass would support the idea that the seizure focus lies somewhere outside of the brain tumor, or extends beyond the brain tumor to include surrounding tissue.3 The fact that seizures are common with brain tumors, such as meningiomas, which do not infiltrate surrounding brain tissue, but simply compress or distort surrounding brain tissue, also supports the idea that seizures originate in the tissue surrounding the brain tumor. Indeed, the tissue surrounding a brain tumor has been shown to differ from normal brain tissue with respect to structure and chemical activity.

It is also possible that the seizure focus lies in areas of the brain that are distant from the tumor.These regions have been found to show seizure-like activity, adding more uncertainty to the debate surrounding the origin of tumor-associated seizures.

Conclusion

Because seizures can be one of the main side effects of having a brain tumor, it is crucial that patients understand what a seizure is, what causes it, and what can be done to treat it.There are many types of medications that are highly effective in treating seizures. Many of the newer medications are as effective as the older ones and have fewer side effects. With ongoing research, we are gaining a better understanding of brain tumors and their associated seizures. A better understanding of these disorders will lead us closer to a cure.

1: Lote K, Stenwig AE, Skullerud K, Hirschberg H: Prevalence and prognostic significance of epilepsy in patients with gliomas. Eur J Cancer 34:98-102, 1998.Tandon PN, Mahapatra AK, Khosla A: Epileptic seizures in supratentorial gliomas. Neurol India 49:55-59, 2001.Beaumont A, Whittle IR: The Pathogenesis of Tumor Associated Epilepsy. Acta Neurochir 142:1-15, 2000.
2: Blümcke I, Wiestler OD: Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. Journal of Neuropathology and Experimental Neurology 61(7):575-84, 2002.
3: Elger CE: Epilepsy: disease and model to study human brain function. Brain Pathol 12:193-98, 2002.Zentner J, Hufnagel A, Wolf HK, et al: Surgical treatment of neoplasms associated with medically intractable epilepsy. Neurosurgery 41:378-86, 1997. 

Mechanisms Underlying Human Mesenchymal Stromal Cell Recruitment and Migration to Human Glioma

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Lata Menon, PhD, Brigham and Women's Hospital, Harvard Medical School

Lata Menon, PhD,
Brigham and
Women’s Hospital,
Harvard Medical
School

A fundamental reason for the failure of many potential therapies for glioblastoma (GBM) is the infiltrative manner in which GBM cells grow, resulting in recurrence. Previous studies (funded by the BSF) indicate that bone marrow-derived mesenchymal stromal cells (MSCs) represent a potential cell based delivery system for therapeutic agents. Lata Menon, PhD, has developed a therapeutic approach to modify MSCs to secrete therapeutic proteins.

MSC exhibit homing property enabling their migration to sites of tumor. Identifying the factors mediating MSC migration will be helpful to achieve enhanced tumor targeting and secretion of drug at the target location, thereby increasing the therapeutic efficacy.

In 2010, Dr. Menon will investigate and identify the signals that influence or/and recruit MSC towards gliomas. A better understanding of the factors that govern and stimulate tumor-specific MSC migration will thus provide potential information for tumor specific targeting. Unraveling the mechanisms that allow MSC to migrate towards the infiltrate tumor cells may provide identification of novel therapeutic targets for enhanced site specific MSC migration. This is a novel treatment approach for a disease in which outcomes are exceptionally poor and options are limited. Only by developing innovative therapeutic approaches such as this will we improve survival and quality-of-life for patients with this devastating neoplasm.

Phase II Meningioma Therapy Trial I

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Patrick Wen, MD, Brigham and Women’s Hospital, Dana-Farber Institute, Harvard Medical School

Patrick Wen, MD,
Brigham and Women’s
Hospital, Dana-Farber
Institute, Harvard
Medical School

In 2010, the BSF will continue its support of correlative studies critical to a phase II study of Sunitinib in patients with recurrent or inoperable meningiomas.

Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) play an important role in the biology of meningiomas. Sunitinib (Sutent) is an oral small molecule inhibitor of the VEGF and PDGF receptors and has therapeutic potential in these tumors. Dr. Wen is leading a phase II clinical trial of Sunitinib in patients with recurrent meningiomas in collaboration with colleagues at Memorial Sloan Kettering Cancer Center (MSKCC). The trial will be stratified into a Grade I meningioma group and a combined Grade II/III meningioma group. The primary endpoints are response rates and 6-month progression free survival. A total of 50 patients will be evaluated.

The correlative studies funded by the BSF are critical to this clinical trial. as they aim to: 1) Correlate the genotype of the tumors with response i.e. we will determine whether specific genetic changes in the tumor predict which patient will best respond to this drug; 2) Perform dynamic-contrast enhanced MRIs to determine the effect of Sunitinib on tumor blood vessels and whether this will help predict who will respond to treatment; 3) Measure serum angiogenic peptides to determine the effect of Sunitinib on these angiogenic factors. In addition, these studies will help Dr. Wen and his team determine what factors are turned on when the tumor becomes resistant to therapy. This will help decide the best strategies to pursue in the next generation of studies.

New Drug Therapies for Meningioma

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Patrick Wen, MD,
Brigham and Women’s
Hospital, Dana-Farber
Institute, Harvard
Medical School

Most meningiomas are effectively treated by surgery and radiation therapy. However, there is an important subset of patients for which these treatments are ineffective. Chemotherapies such as hydroxyurea and alpha interferon are only of marginal benefit. There is an urgent need for more effective treatments for patients who have failed surgery and radiation therapy. Meningiomas are very vascular tumors that express high levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Blocking the receptors for VEGF and PDGF is a potentially promising strategy to treat these tumors.

With the support of the Brain Science Foundation, Dr. Wen and his team are currently conducting a phase II trial of sunitinib (Sutent) for patients with all grades of recurrent meningiomas, as well as hemangiopericytomas. Sunitinib is an oral targeted molecular drug that blocks the receptors for VEGF and PDGF. This study is being conducted in collaboration with Memorial Sloan Kettering Cancer Center. In addition to determining the effectiveness of this approach, Dr. Wen will be studying the patients’ tumors in the hope of identifying the molecular changes that will predict which patients will respond best to this treatment.