Category Archives: Research Projects

Meningioma Stem Cells

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Studies in several cancers (including brain, breast, prostate, ovarian, skin) suggest that only a small fraction of the cells within each tumor is capable of giving rise to another tumor. These tumor-initiating cells (also called cancer stem cells) are thought to be responsible for tumor development and recurrence and have been shown to be more aggressive and resistant to therapy than the bulk of the cells within tumors. It is not known whether meningiomas contain such cancer stem cells. Dr. Johnson’s laboratory is working to determine whether cancer stem cells exist in meningiomas. His goal is to isolate these cells and to characterize their properties using laboratory research and animal models.

Dr. Johnson’s work offers the promise of specifically studying the small proportion of meningioma cells that are responsible for meningioma growth and recurrence. A better understanding of what makes these cells different from other meningioma cells may help us to find new therapies for the treatment of meningiomas.

Oncogenomics of Meningioma

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Mark Johnson, MD, PhD, Brigham and Women's Hospital, Harvard Medical School

Mark Johnson, MD, PhD,
Brigham and Women’s
Hospital, Harvard Medical
School

Meningiomas are the most common primary brain tumor, affecting nearly 1% of the population. Although most meningiomas are slowly growing benign tumors, between 10 and 20% are more aggressive lesions that can recur or progress to a malignant state, resulting in significant disability or death. Surprisingly, however, little is known about the molecular factors contributing to aggressive clinical behavior in meningiomas. To investigate this matter, Dr. Johnson’s laboratory is performing high resolution DNA and RNA genomic analyses of primary human meningiomas of all grades.

Rona Carroll, MD, PhD Brigham and Women's Hospital, Harvard Medical School

Rona Carroll, MD, PhD
Brigham and Women’s
Hospital, Harvard
Medical School

Preliminary studies have revealed the presence of novel genomic alterations affecting numerous oncogenes and tumor suppressor genes in meningiomas. Interestingly, many of these genes are related to the PI-3 kinase/AKT growth regulatory pathway, and contribute to the growth of these tumors. In addition, Dr. Johnson’s team is studying these very large data sets to identify predictors of aggressive clinical behavior in meningiomas that otherwise look benign under the microscope. An increased understanding of the molecular basis for aggressive clinical behavior in meningiomas may lead to the identification of new factors that are useful for prognosis and therapy.

Meningioma Genome Wide Association Study: Development of Pilot Data

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

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

Dr. Claus’s most recent project represents the first effort, worldwide, to obtain pilot data for a genome wide association study for meningioma. It will also attempt to replicate recent preliminary findings of an association between meningioma risk and a BRCA1-associated protein.

Meningiomas account for approximately 30% of all intra-cranial tumors, yet little is known regarding the risk factors associated with these lesions. In an effort to better define such factors, Dr. Claus is performing a nation-wide case/control study of meningioma. This study will include a minimum of 3,200 subjects drawn from Massachusetts, Connecticut, North Carolina, California, and Texas.

At present, the National Institutes of Health (NIH) are funding identification and interview of study subjects as well as the collection of biological specimens for these subjects. No funding exists for the genetic analysis of these specimens. The goal of the current BSF project is to perform the first genome wide association study (GWAS) of meningioma using 200 cases in the above mentioned case/control study. These data will be used as pilot data towards a larger NIH application to perform a GWAS on the entire data set.

The specific aims of this project are to:

  • Perform a genome wide association study for meningioma on the first 200 cases drawn from Dr. Claus’s larger meningioma case/control study.
  • Attempt to replicate Dr. Claus’s Gliogene collaborators finding of a link between meningioma risk and BRIP1, breast cancer susceptibility gene (BRCA1)-interacting protein 1.

Identification of Essential Kinases in Meningioma by RNA-Interference

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Dr. Ian Dunn, MD

Dysregulated kinase activation plays an essential role in the genesis of most, if not all, human cancers. The identification of kinases that drive oncogenic growth represents a highly attractive strategy for selectively targeting malignant cells. For example, the identification of the BCR-ABL kinase in chronic myelogenous leukemia and the spectacular clinical success of its targeting by imatinib show the potential clinical impact of this approach. Despite a few recent successes, we still lack a comprehensive knowledge of the number and identity of kinases whose activity is essential for the transforming events and maintenance of human cancers.

This is particularly true in meningioma. In part, this deficiency exists because we have lacked the tools to study kinase signaling pathways systematically. Dr. Dunn’s project details the application of a novel genetic approach, RNAi-interference (RNAi), to meningioma cell lines to identify functionally relevant cancer-associated genes which are required for meningioma cell survival. RNAi suppresses the expression of genes in a specific manner, permitting the study of the functions of one or many genes. Potential applications of RNAi to the study of human cancer are broadening: experiments involving gene knockouts to determine gene function may now be carried out in the majority of human cell types, and thousands of genes may be studied in a very reasonable period of time. In a systematic fashion, we hope to identify kinases which are essential for the survival of meningioma cell lines. As our RNAi library expands, we hope to extend this approach to the study of the majority of genes in the human genome in order to determine genetic function in these tumors. This strategy is thus immediately translational in that candidate genes emerging from the screen which are essential to the survival of meningioma cell lines immediately become therapeutic targets.

In addition, recent studies have focused on the potential therapeutic applications of RNA interference. For instance, the ability to silence disease-associated genes in a sustained manner with RNA interference is being explored in a host of cancers and infectious diseases. Thus, RNA interference may provide an efficient and powerful method of elucidating the genetic participants in meningioma and may ultimately represent a viable therapeutic option in their treatment.

Identification of Genomic Alterations Underlying Non-NF2-related Initiation of Meningioma Tumorigenesis

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Dr. Michel Kalamarides, PhD

Meningiomas are common central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Around 50% of patients with Neurofibromatosis 2 (NF2) develop meningiomas. The NF2 gene is also involved in sporadic meningiomas: 60% show inactivation of this gene.

In a previous study funded by the BSF, Dr. Kalamarides analyzed the genetic mechanisms underlying tumor progression in meningiomas. He used a new powerful technology: the 500K Single Nucleotide Polymorphism array (500K SNP), the latest version gene mapping array. By comparison of the genomic differences between low grade and high grade meningiomas in the same patient, Dr. Kalamarides identified molecular mechanisms involved in tumor progression (paper under preparation). He showed that 2 major groups of meningiomas are clearly different, based on the NF2 gene status. However, the genetic initiation remains unclear in 40% of meningiomas without NF2 gene mutation.

In this present study, Dr. Kalamarides aims to identify candidate genes involved in meningioma tumorigenesis initiation. He will conduct a whole genome 500K SNP analysis on 40 benign meningiomas, 20 with normal NF2 protein and 20 with mutated NF2 protein. By comparison of their genomic differences (and control blood), Dr. Kalamarides will be able to identify candidate genes that are independent of NF2 and involved in tumor initiation.

Ultimately, the identification of these putative genes will lead to better understanding of the molecular mechanisms underlying non-NF2 related meningioma tumorigenesis (40% of meningiomas), to generate additional animal models and to identify new potential therapeutic targets.

Intraoperative Mass Spectrometry for Personalized Treatment of Brain Tumors

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Dr. Agar has recently set up a new laboratory at BWH, oriented towards the validation and implementation of spectroscopic applications to serve surgical and clinical needs in cancer patient care. The interdisciplinary laboratory structure is innovative in itself as it is the fruit of a concerted effort between the Departments of Neurosurgery, Radiology, and Pathology at BWH to create an environment capitalizing on cross-discipline approaches to expedite progress in personalized medicine. The laboratory will soon harbor high-end mass spectrometers, as well as an NMR magnet dedicated to clinical magnetic resonance spectroscopy (MRS), and a specialized microscope scanner to allow telepathology and validation of spectroscopic approaches to the gold standard of histopathology.

Dr. Agar’s own multidisciplinary training has evolved from B.Sc. in Biochemistry, Ph.D. in Chemistry, Postdoctoral training in Neurology and Neurosurgery from McGill University, and Postdoctoral training in Neurosurgery at the Brigham and Women’s Hospital in the laboratory of Dr. Peter Black. Through this distinctive training, she has acquired knowledge and developed skills to better understand requirements and limitations related to technology implementation from the instrumentation standpoint, to sample and data analysis, to cancer and surgical needs, and to medical environment.

The scope of her initial project supported by the Brain Science Foundation is the development of a rapid, accurate, and high-throughput approach for characterizing meningiomas and other brain tumors at the molecular level at the time of surgery. The technology, called Matrix Assisted Laser Desorption Ionization (MALDI) Mass Spectrometry Imaging (MSI), provides information on hundreds of proteins from frozen tumor tissue in minutes.

Biochemical factors responsible for tumor development, maintenance, and progression vary from one cancer to another, as well as from one patient to another. A comprehensive molecular diagnosis obtained during surgery will enable surgeons to tailor treatment during surgery by knowing how aggressive and invasive a tumor may be by its biochemical profile, and can form the basis for adjuvant therapy such as chemotherapy including agents given into the tumor cavity at the time of surgery, and will orient the choice of chemotherapy given systemically.

With prognosis being intimately related to the appropriateness of treatment modality, identifying and grading tumors with such high sensitivity and molecular accuracy would maximize treatment efficacy. Current diagnosis and treatment rely upon observations of tissue and cellular characteristics such as proliferation, cellular and nuclear morphology, vascularization, and specific available biomarkers. Current histopathological approaches would certainly be augmented by the proposed detailed molecular profiling.

BSF awarded funding for this project in 2009 and 2010.

Meningioma MRI Imaging

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Most meningiomas are slowly growing lesions of which 90% are classified as benign. Neurosurgeons generally avoid operating on patients with small meningiomas, particularly those which are difficult to access surgically and prefer to carefully monitor tumor growth. Monitoring includes neurologic evaluation and periodically acquiring Magnetic Resonance (MR) scans of the patient’s brain. In clinical practice, finding evidence for subtle growth from MR scans can be very difficult, particularly between scans taken at relatively short intervals.

To address this gap, Dr. Kikinis has developed a semi-automatic procedure, called ChangeTracker, specifically targeted towards identifying difficult-to-detect changes in pathology. ChangeTracker is easy to calibrate and, in less than five minutes, returns the total area of tumor change in cm3. Dr. Kikinis has tested the tool on postgadolinium, T1-weighted MRI acquired through a standard clinical acquisition sequence. The tests indicate that ChangeTracker is more accurate in detecting subtle growth than current clinical procedures. This approach is disseminated as part of the 3D Slicer, a publicly available software package targeted towards medical imaging processing and visualization.

In 2009, Dr. Kikinis plans to further develop, maintain, and disseminate the ChangeTracker. It is his hypothesis that the development will further increase the robustness of ChangeTracker in identifying subtle growth that would have gone unnoticed by current clinical procedures. Dr. Kikinis will also assess the ability to analyze multiple time points.

Genetically Modified Human Mesenchymal Stromal Cells (hMSC) as a Therapeutic Delivery Vehicle for Brain Tumors

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Dr. Menon’s research is focused on developing new cell based drug delivery systems for continuous delivery of drug/biological agents at tumor site. Two major concerns in cancer therapy are the short half-life, availability or excessive toxicity of the drugs, and the extreme invasiveness of the malignant tumor cells to infiltrate into the surrounding tissue and recur locally near the neurosurgical resection site. The goal is the direct targeting and eradication of these disseminated tumor cells in the brain. Stem cell-based therapies provide a promising approach for treatment of tumors in humans. Human bone marrow derived mesenchymal stromal cells (hMSC) is an excellent source, as these cells can be genetically modified to express proteins/drugs and also have an exceptional migratory or homing ability towards tumors, injury or inflammation.

This project will study the use genetically modified human mesenchymal stromal cells as a local therapeutic drug delivery vehicle for the targeted delivery and secretion of chemotherapeutic/biologic agents for treatment of brain tumors. This therapeutic strategy employs genetic modification of hMSC and exploits the tumor tropic behavior, for tracking to sites of tumor cell invasion and allows on-site generation of drug to control tumor growth. This approach will allow the cells to migrate to dispersed tumor cells near the surgical site and also to track down tumor cells migrated to the normal brain parenchyma.

For this study, hMSC will be genetically engineered to express a prodrug enzyme, Cytosine Deaminase (CD). CD is an enzyme found in bacteria and fungi that converts nontoxic drug 5-fluorocytosine (5-FC) to form the highly cytotoxic 5-fluorouracil (5-FU). The 5-FU produced locally will diffuse through cellular membranes thereby increasing the cytotoxicity to neighboring tumor cells without increasing the risk of harmful systemic effects. This is a novel treatment approach for a disease in which outcomes are exceptionally poor and options are limited. Developing innovative therapeutic approaches can help us to improve survival and quality-of-life for patients with this devastating neoplasm. hMSC is an ideal candidate and compatible for clinical use as these cells can be harvested by bone marrow aspiration from individual patients without difficulty, processed ex vivo very efficiently, and later transplanted back into the same patients during surgery thereby reducing immunological consequences.

The results at the conclusion of this project will provide us all the information necessary for a pilot phase I feasibility and safety study for treating brain tumor patients with mesenchymal stem cells that have been engineered to express cytosine deaminase (MSC-CD) followed by 5-FC therapy.

Advanced Functional and Structural Brain Mapping for Neurosurgical Planning and Intra-operative Decision Making

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Alexandra J. Golby, MD Brigham and Women's Hospital, Harvard Medical School

Alexander J. Golby, MD
Brigham and Women’s
Hospital, Harvard
Medical School

Surgery remains the single most effective treatment for patients with brain tumors. For many types of tumors surgery is able to improve symptoms, relieve seizures, and provide a great decrease in the amount of tumor, making further therapies more effective. The work of the Golby Lab centers on using imaging to improve neurosurgical treatment of brain lesions. Dr. Golby’s work uses multiple imaging approaches to give the surgeon maximal information for pre-operative planning and intra-operative decision-making. The Golby lab is grateful to the Brain Science Foundation for supporting its work using multiple imaging approaches to optimize surgical resection in patients with brain tumors.

Tumors located near critical brain areas such as areas that control movement, speech, vision or other important functions, pose a great challenge as neurosurgeons must remove as much of the tumor as possible while sparing the critical brain structures. Unfortunately, the brain does not have any labels on it indicating the key areas. In fact neither conventional imaging nor visualization of the brain itself directly at surgery is able to differentiate which areas of the brain are responsible for performing which functions. In addition, it can be difficult to localize tumors and to define the optimal limits of resection due to the limited information available to the surgeon using only their eyes.

Dr. Golby and team have been developing imaging techniques which can begin to show surgeons functional maps of the brain and to integrate these with intra-operative navigation. These techniques use magnetic resonance imaging (MRI) which is non-invasive and can be readily acquired before surgery. Her group’s efforts have been focused on using two advanced MRI techniques: functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). fMRI is able to show areas in the grey matter (the cortex, where the neurons are clustered), which are activated when the patient performs a certain task. These areas can be superimposed on standard MRI images to show neurosurgeons a detailed functional map which can help to guide surgical decision making. DTI is another technique which is able to show another aspect of brain organization which has previously been invisible to the naked eye. This technique is able to show the arrangement of the white matter in the brain. White matter contains all of the connections between neurons in the cortex and between the cortex and deeper parts of the brain. These connections, called tracts, also have to be spared during surgery in order to avoid causing harm to the patient. By showing the configuration of these connections DTI can aid the neurosurgeon in determining whether they have been displaced, infiltrated or destroyed by the tumor thus helping to guide the resection strategy. While these functional and structural brain imaging techniques provide an unprecedented view into the structure-function relationship of the human brain, there remain many unanswered questions as to the best approaches which are valid, reliable, and helpful to the surgeon.

With funding from the BSF, Dr. Golby has made some significant strides in addressing some of these problems, while at the same time introducing new questions. Her present work is focusing on two new goals: (1) to allow the demonstration of specific white matter tracts by selecting or seeding from key cortical regions and (2) translation of a new approach using connectivity analysis in fMRI data to allow definition of key cortical regions without requiring the performance of a behavioral task.

Beyond pre-surgical planning, intra-operative delineation of resection margins can be difficult because tumors resemble brain, often infiltrate brain tissue, may be immediately adjacent to critical functional brain tissue, and deformation of brain structures occurring intra-operatively renders pre-operative images less helpful. Dr. Golby’s lab is developing several systems which can be deployed intra-operatively to assist neurosurgeons in clearing margins of residual brain tumor tissue following bulk tumor resection.

The Role of Cdc20 in Cerebellar Granule Cell Precursor and Medulloblastoma Biology

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Dr. Albert H. Kim, MD, PhD
Primary brain tumors represent the most common solid tumor of childhood. Among these, medulloblastoma is the most frequently observed, accounting for nearly 20% of all pediatric brain tumors. Despite recent overall improvements in patient survival with current treatments, the five-year event-free survival rate remains 20% in a substantial number of patients severely afflicted with this disease. An emerging theme in cancer biology is that the dysregulation of normal developmental signaling pathways contributes to cell transformation. Consequently, elucidation of the pathways controlling proliferation, differentiation, and survival of the medulloblastoma cell-of-origin is likely to provide insights into tumor pathogenesis. Pathological and microarray evidence suggests that the cell-of-origin for medulloblastoma is the cerebellar granule cell precursor (GCP).

Dr. Kim has recently uncovered a novel role for Cdc20, a component of the major mitotic regulator, the anaphase-promoting complex (APC), in the development of postmitotic neurons along the GCP lineage. Using an RNA interference-based approach, he has discovered in cerebellar granule cells in vivo that Cdc20 is required for the formation of dendrites, the critical receptive limb of neuronal circuits. Dr. Kim’s current project will not only investigate the molecular basis for Cdc20’s essential function in dendrite morphogenesis but also test the role of Cdc20 in GCP and medulloblastoma proliferation.

The underlying hypothesis of this project is that insights into normal GCP development will reveal mechanisms of medulloblastoma pathogenesis. An improved molecular understanding of medulloblastoma tumorigenesis is required for the development of specific signaling pathway-targeted therapies and patient-tailored treatment.

Elucidation of Minocycline-induced Alternative Extrinsic Apoptosis Pathways in Brain Tumor

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Dr. Shan Zhu, PhD
Minocycline is an FDA approved antibiotic and was recently found to inhibit angiogenesis/vasculogenesis, which is important for tumor growth and metastasis. In a murine glioblastoma model, treatment with minocycline delivered intracranially at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. However, the detailed mechanism underlying such dramatic effect of minocycline is still unknown.

Dr. Zhu will focus on the basic mechanism of minocycline inside the tumor cells based on his previous findings about induction of cell apoptosis (self-controlled cell death program) by minocycline with a yet unidentified pathway. Defining the molecular physiology of alternative apoptotic pathway will improve our understanding of tumorigenesis. The resulting information will help understand the role of minocycline in the treatment of brain tumors and provide additional therapeutic strategies, development of new drugs, benefit patients suffered from brain tumors and other tumors as well.