2010 Research Projects
A Pilot Trial of Cytosine Deaninase-Expressing Mesenchymal Stromal Cells in Glioblastoma Therapy, Peter Black, MD, PhD
Funded in collaboration with the Daniel E. Ponton Fund for the Neurosciences at Brigham & Women's Hospital
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.
Mechanisms Underlying Human Mesenchymal Stromal Cell Recruitment and Migration to Human Glioma, Lata Menon, PhD
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.
Semi-Automatic Identification of Neurosurgically Important White Matter Tracts Using fMRi + DTT Atlas, Alexandra Golby, MD
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.
The Role of the cdc20-Anaphase Promoting Complex Signaling Pathway in Cerebellar Granule Cell Precursor Development and Medulloblastoma Migration, Albert Kim, MD, PhD
Funded in collaboration with the Daniel E. Ponton Fund for the Neurosciences at Brigham & 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.
Intraoperative Mass Spectrometry for the Personalized Treatment of Brain Tumors, Nathalie Agar, PhD
Surgery remains the most important and usually the first form of treatment for brain tumors, with prognosis associated with the surgeon’s ability to maximize the resection of a tumor while minimizing the potential for neurological deficit. Dr. Nathalie Agar and her team are harnessing the power of the latest imaging technology to detect the margins of a tumor at the molecular level, and to provide tissue analysis that would enable surgeons to analyze tumor properties during surgery. Her research has the potential to improve the tailoring of personalized treatments from diagnosis to surgery and the administration of subsequent therapies such as chemotherapy.
DNA Repair Mechanisms as Targets for Therapy of Pituitary Adenomas, Edward Laws, MD
Funded in collaboration with the Daniel E. Ponton Fund for the Neurosciences at Brigham & Women's Hospital
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.
Phase II Meningioma Therapy Trial I, Patrick Wen, MD
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.
Oncogenomics of Meningioma, Mark Johnson, MD, PhD
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 to further identify the genomic alterations underlying clinically aggressive behavior in meningiomas. Increased understanding of the genetic and cellular basis for aggressive behavior in meningiomas may lead to the identification of clinically-relevant prognostic variables and novel molecular targets for therapy.
Familial Study of Meningioma, Elizabeth B. Claus, MD, PhD
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, 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.
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.