Brain Science Foundation’s principal investigator, Elizabeth Claus, MD, PhD*, and her team, recently published two articles on Meningiomas.

The first article, titled Quality of “Life After Surgery for Intracranial Meningioma“, appeared in the January edition of the journal Cancer.

The second article, titled “Genome-wide association analysis identifies a meningioma risk locus at 11p15.5“, appeared in the May edition of Neuro-Oncology.

Doctor Claus states; “Our group has recently published two articles on Meningioma with a third accepted – all done with support from the Brain Science Foundation… As always – thank you for your support!”

*Elizabeth B. Claus, MD, PhD
Professor and Director of Medical Research
Yale School of Public Health
Attending Neurosurgeon
Brigham and Women’s Hospital

Brain Science Foundation funded investigator, Dr. Brastianos, is running a Meningioma trial in collaboration with the National Cancer Institute sponsored group called the Alliance. There are now more than 400 other entities throughout the U.S. participating. The principal physicians and researchers collaborating are tremendously hopeful that this trial will be a paradigm shift in the management of brain tumors.

The Brain Science Foundation has long supported Dr. Elizabeth Claus’s research exploring the causes of meningiomas. She recently published her study linking certain kinds of dental X-rays and meningiomas in the American Cancer Society journal Cancer.

The study focused on bitewing X-rays performed in the 1960s, which used a much higher level of radiation than today. Dr. Claus and her team worked with 1,433 persons diagnosed with a meningioma, many of whom were brought into the study with the help of the Brain Science Foundation. Dr. Claus is not advocating people avoid going to the dentist, however. As she told the Boston Globe, “The broader public health message is that probably the increase in risk to a given individual, given the current dose [of radiation exposure] is low. But you could say, gee, if this is a primary exposure in the US and we can lessen the exposure, [that is something worth considering].”

Dr. Claus, a professor at the Yale School of Public Health and a neurosurgeon at Brigham & Women’s Hospital, noted that risk factors for meningioma, the most common primary brain tumor, remain poorly understood. This is in part because meningiomas were only added to brain tumor registries in the United States in 2004.

The Brain Science Foundation awarded Dr. Claus an additional grant in 2011 exploring the genes involved in radiation-associated meningiomas.

Dr. Claus will attend both days of the upcoming Meningioma Awareness Day and will also be signing up new volunteers for future reasearch studies.

For nearly 10 years, the Brain Science Foundation has driven research into the causes, treatment, and understanding of meningioma tumors. In fact, the foundation launched to fill the need for innovation in this poorly understood and understudied brain tumor.

We continue our commitment to finding a cure and advancements in meningioma understanding. The following meningioma projects are currently underway:

• Genes for Radiation-Associated Meningioma
  Elizabeth Claus, MD, PhD
• Investigating Meningioma Recurrence with the Comprehensive Resources of the Nurses’ Health Study
  Sandro Santagata, MD, PhD
• Reconstructing the Meningioma Genome
  Rameen Beroukhim, MD, PhD
• Identifying Transcription Factor Targets in Meningioma: A Non-Oncogene Approach
  Sandro Santagata, MD, PhD
• Development of a Natural Viewing Paradigm for fMRI Language Mapping for Brain Tumor Surgery Planning
  Yanmei Tie, PhD

Visit our Project Archive to see past projects, many of which focus on meningiomas and related areas.

What’s New

10 Years of Success

• 80 Research Projects and Counting
• A total of $12 million in direct research funding
• An additional $40 million in support leveraged by investigators from other sources to continue their work

We are elated to announce that in 2015 the BSF began its support of a clinical new initiative. Using BSF funds, Investigators: Priscilla Brastianos, MD; Ian Dunn, MD; Sandro Santagata, MD; and Rameen Beroukhim, MD discovered novel recurrent mutations in Meningiomas that will have significant impact on the future treatment of these tumors. These mutations are known genetic targets in other cancer types but had never been described in Meningiomas until now. In 2015, BSF funded investigator Dr. Brastianos will lead a far reaching, multi-institutional Phase II Study looking at inhibitors that target these mutations. This will be the first ever trial of personalized drug therapies for Meningiomas, and represents a paradigm shift in Meningioma therapy!

Priscilla Brastianos, MD, won her first ever research grant from the BSF in 2011. Since then, Dr. Brastianos’ work has grown, garnering additional support for her research. In 2015, she and her team launched the first ever trial of personalized drug therapies for Meningiomas.

Peleg Horowitz, MD, PhD

Schwannomas are a diverse group of brain tumors that cause symptoms by progressively and unrelentingly compressing and displacing the normal brainstem and cranial nerve anatomy at the skull base. Most schwannomas are slow growing, but their clinical impact on patients isanything but benign: symptoms progress from ringing in the ears, imbalance, and hearing loss to facial dysfunction, brainstem compression, and early death. The intimate relationship of these tumors to nerve fibers controlling facial expression and hearing makes their treatment challenging.

Treatments for many other tumor types have arisen from an understanding of the subtle differences between tumor and normal cells. Particularly important are changes in the genetic code that serve as a blueprint for how cells should behave. Early studies into the genetics of schwannomashave shown frequent disruptions of a gene called NF2 that encodes a tumor suppressor; however, no treatments currently exist that target NF2 directly.

A major barrier to more effective treatments is the lack of understanding of the genetic events outside of NF2 in these tumors. Preliminary findings suggest that other parts of the genome may be important as well. This project will perform an in-depth, comprehensive study of the genomes of several schwannomas to fully characterize the genetic alterations in these tumors. Such changes may be in the form ofsubtle mutations (“typos” in the genetic code), larger deletions or insertions, or even massive genetic rearrangements that give tumor cells a particular growth advantage over normal nerve sheath cells. These findings will then be verified with a focused study of a much larger group of schwannomas. Dr. Horowitz and his team hope that this study will uncover important new genetic changes that drive schwannoma growth and development, pointing the way to new treatment strategies.

Elizabeth Bradshaw, PhD

Little is known about the immune response to meningiomas, even though a robust infiltration of a specific immune cell type, monocytic cells, has been described. Understanding the role of the infiltrating immune cells in meningiomas is critical for future applications of immunotherapy.

Little is known about the immune response to meningiomas, even though a robust infiltration of a specific immune cell type, monocytic cells, has been described. Understanding the role of the infiltrating immune cells in meningiomas is critical for future applications of immunotherapy.

Little is known about the immune response to meningiomas, even though a robust infiltration of a specific immune cell type, monocytic cells, has been described. Understanding the role of the infiltrating immune cells in meningiomas is critical for future applications of immunotherapy.

Little is known about the immune response to meningiomas, even though a robust infiltration of a specific immune cell type, monocytic cells, has been described. Understanding the role of the infiltrating immune cells in meningiomas is critical for future applications of immunotherapy.

Immune cells are highly adaptable to their environment and respond to signals from surrounding cells causing them to change how they appear and behave. Monocytic cells can either enhance orsuppress tumor growth, depending on the signals they receive from their environment. It is thought that the tumor cells themselves can influence the behavior of the monocytic cells, making them a potential therapeutic target.

Dr. Bradshaw and her team hypothesizes that the monocytic infiltrate in meningiomas is highly heterogeneous, and part of it is composed of myeloid-derived suppressor cells, which potently prevent the immune system from attacking the tumor. Myeloid-derived suppressor cells themselves are very diverse in the markers that identify them and in how they suppress immune cells. This heterogeneity may reflect the heterogeneity of the various tumor types thatinduce them. The team will determine what sub-types of monocytic cells exist in meningioma, both pro- and anti-tumor, what role they are playing in suppressing the immune system from attacking the tumor and how the tumor cells control their behavior. Such findings could lead to novel strategies to modulate the immune system to enhance its effectiveness in managing tumor growth.

Ursula Kaiser, MD

Pituitary tumors are among the most commonly occurring neoplasms of the central nervous system, comprising approximately 15% of intracranial tumors. Although typically benign, they cause significant morbidity through mass effects and/or the inappropriate secretion of pituitary hormones, resulting in loss of vision, infertility, growth disorders, and metabolic disturbances.

The causes of pituitary tumor formation have been studied extensively, but the mechanisms involved in pituitary cell transformation remain elusive. Hormones and growth factors that modulate normal pituitary development and endocrine activity have been implicated in pituitary tumor growth, but do not appear to be the initiating cause. Mutations of tumor suppressor genes or oncogenes, as seen in more common cancers, do not seem to play an importantrole in the majority of pituitary adenomas. Recent evidence from Dr. Kaiser’s lab suggests that epigenetic histone modifications may play important roles in pituitary tumor pathogenesis.

Epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. Dr. Kaiser and her team plans to leverage the unique resources of the Brigham & Women’s Hospital Pituitary/Neuroendocrine Center and the associated comprehensive pituitary tumor tissue bank to further investigate the contributions of such epigenetic histone modifications to the formation of pituitary adenomas. Epigenetic studies in these tumors can lead not only to new insights into the pathophysiology of pituitary adenomas, but can in turn provide insights into the mechanisms underlying other cancers. These studies are also likely to help us understand why these adenomas do not progress tomalignant carcinomas in most cases, and may help us understand pathways that restrain the progression of pituitary tumors from benign to malignant neoplasms, which may have significantly broader implications for other tumor types.

Nadiya M. Teplyuk, PhD
Glioblastoma (GBM, or glioma of grade IV) is one of the most common and aggressive brain cancers with poor survival rates even with intensive treatment. Increasing evidence suggests that GBMs derive from glioma initiating cells (so-called cancer stem cells), which originate directly from neural stem cells in the process of malignant transformation. Therefore, targeting GBM initiating cells is important for reducing GBM growth. However, molecular events that lead to the transformation of normal neural progenitors to GBM-initiating stem cells are poorly understood.

Recent discovery of microRNAs, small regulatory RNA molecules, revolutionized the field of cancer biology. Since a single microRNA may control expression of multiple cellular proteins, de-regulation of one or a few microRNAs may lead to aberrant intracellular metabolism and cancer growth. Dr. Teplyuk and her team’s work over the past few years focused on the discovery of microRNAs that contribute to glioma initiation and progression, gathering mounting evidence indicating that microRNAs are essential regulators of GBM growth. The team has recently identified a specific microRNA, miR-10b, not expressed in normal brain cells, including neural stem cells. This same molecule is abundant in tumorigenic glioma-initiating stem cells, suggesting that miR-10b activation is an early event in the origin of a glioma. We found that miR-10b drives glioma cell division and may function as a molecule that promotes GBMs.

This project hypothesizes that induced expression of miR-10b in neural stem cells can cause malignant transformation. As miR-10b is highly specific target for GBM, we anticipate this work will set a background for development of a new therapeuties to use against GBMs.

Erik Uhlmann, MD; Anna Krichevsky, PhD

This project investigates key microRNA targets for possible meningioma treatments. The high prevalence of meningioma translates to high burden of disease with significant impact on quality of life. Initial treatment may consist of surgery, if technically feasible and medically tolerated. However, surgery alone rarelyremoves all tumor tissue, owing to its extension along the meninges. For patients with recurrent disease, or at high risk of recurrence, there is a need for targeted medical therapy, presently unavailable. This team hypothesizes that microRNAs are critical growth regulators of meningioma cells, and altered microRNA expression in a specific pattern is a key step in meningioma progression. They propose to determine the microRNA expression profiles of grade I and grade II meningiomas, and to identify the differentially expressed microRNAs. These candidate microRNAs will then be tested for their effect on cell growth and meningioma formation. Simply, microRNAs may be effective therapeutic targets for the treatment of meningiomas.

Joseph Madsen, MD

There are currently many robotic surgery technologies in existence, but none for use in the brain. For many brain surgery procedures, endoscopic surgery techniques have greatly improved patient outcomes. This project takes the concepts of endoscopic surgery and goes even smaller—using devices to enter the brain and treat tumors with minimal invasion. This project asks the question “why is brain surgery so invasive?” and attempts to find a solution through the design and development of robotic surgery techniques to treat brain tumors. Dr. Madsen and his team have several years of experience exploring this very process and will use this project to apply new advances in robotic surgery to the brain.

Rameen Beroukhim, MD, PhD; Ian Dunn, MD

Surgery is frequently insufficient for people with grade II–III meningioma tumors. For these people, no effective medical therapies exist. As part of a previous BSF funded study, this team examined several meningioma genomes, finding multiple genetic events, copy-number changes, and mutations with immediate clinical implications. Their study also showed that grade II and III tumors may be completely different diseases from grade I meningiomas. This project hypothesizes that genes found to be mutated in grade I meningiomas are also mutated in higher-grade meningiomas alongside mutations in additional genes. The team will perform whole-exome sequencing of 12 grade II and III meningiomas. They will then identify mutations affecting all genes in these tumors. Secondly, they willtest the hypothesis that high-grade meningiomas have higher rates of mutation, rearrangements, and copy-number changes genome-wide than grade I tumors. They will perform whole-genome sequencing of at least two grade II–III meningiomas, completely reconstructing these genomes, identifying all mutations and rearrangements both within and between genes. These studies will form a foundation for understanding why grade II–III meningiomas develop and could bring about potential therapeutic targets.

Elizabeth Claus, MD, PhD

Dr. Claus and her team

The development of meningioma is likely related to both genetic and environmental risk factors. Ionizing radiation (IR) is one of the few consistently identified environmental risk factors for meningioma development. At high dose levels, data exist for atomic bomb survivors as well as for cancer patients who have received radiation to the head, particularly at a young age, and show a greatly increased risk for meningioma. Evidence also exists for lower dose levels including results from our population-based study which suggests that extended exposure to dental x-rays at a young age may be associated with increased risk of meningioma.

With respect to genetic risk factors, there is considerable evidence that a reduced capacity to repair DNA is associated with increased sensitivity to radiation exposure, risk of development of cancer, as well as clinical prognosis after diagnosis with cancer alone or in association with treatment such as radiation therapy. Research indicates that cells in persons with certain variants in these genes, i.e. DNA repair genes, have more difficulty in repairing damage after exposure to IR and thus are at higher risk of tumors such as meningioma.

In Dr. Claus’ new study, “Genes for Radiation-Associated Meningioma,” she and her team hypothesizes that persons with meningioma exposed to prior IR represent a genetically sensitive sub-population of meningioma patients. Over the next two years, we will compare variants in genes thought to repair DNA damage in two groups: persons with meningiomas who were previously exposed to IR, and persons with similar IR exposure but who have not developed meningiomas. If the hypothesis is true then higher rates of certain variants are expected in a select group of DNA repair genes in persons with meningiomas versus those without meningiomas. If successful, findings might be used to identify persons at increased risk for meningiomas as well as persons for whom radiation therapy may be associated with an increased risk of adverse outcome.

The Brain Science Foundation is proud to support cutting edge research in the neurosciences. In 2010, ten talented physician scientists completed groundbreaking work in the pursuit of a cure. Many of these scientists have been recognized for their work and have received advanced funding, proving that the BSF’s mission to seed novel research is succeeding.
To read more about the outcomes and current status for each of these projects, please download the status reports provided by the principal investigators:

Nathalie Y.R. Agar, PhD
Intraoperative Mass Spectrometry for Personalized Treatment of Brain Tumors
(PDF, 20KB)

Peter Black, MD, PhD & Rona Carroll, PhD
On the Road to a Clinical Trial for Using Gene Therapy for Aggressive Glioblastomas
(PDF, 15KB)

Elizabeth B. Claus, MD, PhD
Genome-Wide Search for Meningioma Genes/Family Study of Meningioma
(PDF, 13KB)

Ian F. Dunn, MD
Comprehensive Identification of Therapeutic Targets in Meningioma
(PDF, 250KB)

Alexandra J. Golby, MD
Semi-automatic Identification of Neurosurgically Important White Matter Tracts using fMRI & DTI Atlas
(PDF, 135KB)

Mark Johnson, MD, PhD
Oncogenomics of Meningioma
(PDF, 10KB)

Albert Kim, MD, PhD
The Role of the CDC20-Anaphase Promoting Complex Signaling Pathway in Cerebellar Granule Cell Precursor Development and Medullablastoma Migration
(PDF, 11KB)

Edward R. Laws, Jr., MD
DNA Repair Mechanisms as Targets for Therapy of Pituitary Adenomas
(PDF, 14KB)

Lata Menon, PhD
Mechanisms Underlying Human Mesenchymal Stromal Cell (MSC) Recruitment and Migration to Human Glioma
(PDF, 22KB)

Patrick Wen, MD
Phase II Meningioma Therapy Trial

Brain metastasis is a common complication in breast cancer and occurs in up to 30% of patients with metastatic breast cancer. With advances in diagnostic techniques and improved treatments, the incidence of this devasting complication is increasing. Of patients with clinically significant brain metastases, the majority die within months. Unfortunately, clinical trials commonly exclude patients with brain metastases. An understanding of the molecular mechanisms of brain metastasis and better treatment approaches are urgently needed.

Cancer arises primarily from the acquisition of alterations in the DNA of cells. Knowledge of these genetic alterations has lead to the identification of new groundbreaking targeted therapies for cancer. Among these are trastuzumab, which targets Her2/neu in HER2+ breast cancer, imatinib which targets bcr-abl in chronic myelogenous leukemia, and PLX4032 which targets BRAF in melanoma. These treatments not only induce significant responses but are much less toxic than traditional chemotherapy. To identify mutations such as these, international efforts to sequence the genomes of many types of cancers are underway. However, most of these efforts do not include metastatic disease despite the devastating clinical impact of this disease.

This study aims to detect the changes in the DNA of metastatic brain tumors in breast cancer. Dr. Brastianos and her team hypothesize that tumors undergo multiple genetic changes that are responsible for brain metastases. Metastasis is a complex multi-step process and these studies will identify mutations responsible for each of these steps. The team will utilize state-of-the-art sequencing technologies at the Broad Institute and the Dana-Farber Cancer Institute to characterize the genomics of brain metastases from breast cancer. The comprehensive identification of somatic genetic events in brain metastases from breast cancer has the potential to transform our understanding of this disease, and will bring us closer to developing targeted approaches to metastatic disease of the brain from breast cancer.

Yanmei Tie, PhD

Brain tumor surgery aims to maximize tumor resection (removal); however, it must weigh and minimize the risk of resection-induced neurological deficits. Preventing injury to language areas is especially important as it can lead to potential lifelong language deficits (known as aphasia). This naturally has an enormous impact on quality of life. Mapping out the language function areas in individual patients poses a challenge due to the high complexity and variability of the brain language network location from patient to patient.

As a clinical non-invasive imaging technique, functional MRI is used to identify language areas by measuring blood oxygen level-dependent (BOLD) signal change while patients perform language tasks (such as generation of antonyms). In short, specific areas of the brain “light up” under MRI when the patient performs basic language tasks.

Although task-based fMRI has been widely used to aid surgical planning, it has shortcomings. First, it requires adequate task performance, which excludes many patients who have difficulty performing language tasks due to neurological deficits (such as aphasia and attention problems). Second, due to the complex language function and patient-specific conditions, a panel of tasks is needed. This requires expertise to design and administer the tasks which are time and cost consuming.

To overcome the limitations of task-based fMRI, Dr. Tie aims to develop a novel fMRI protocol and a corresponding analytic strategy for mapping individual patients’ language areas. This protocol is less demanding, therefore allowing fMRI language mapping for more patients, especially those who cannot perform traditional language tasks. It is also easier for the technologists to administer, and has the potential to provide a comprehensive map of the complex language network, therefore reducing the time and cost of pre-surgical planning. Dr. Tie will collaborate with Dr. Alexandra Golby and Dr. Srinivasan Mukundan, Jr., in the proposed project.