Outcome Reports for Funding Ending in 2016

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Medical Student Summer Fellowship (June – August 2016)

  • Vyshak Chandra

    Massachusetts General Hospital, Boston, MA

     

    Project title:

    "A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor patients treated with chemoradiation or immunotherapy"

    Summary:

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults, and is a fatal disease with 5-year survival rates that are less than 4%, even with aggressive treatment. Immunotherapy, a treatment method that attempts to boost the body’s natural defense system to fight disease, has been recently tested in glioblastoma patients. Our goal was to use new imaging techniques to measure the effectiveness of these immunotherapy treatments in patients with glioblastoma multiforme, and hopefully aid in the fight against this treacherous disease. We studied a new PET imaging tracer, PBR-28, that highlights areas of inflammation in the brain of patients undergoing immunotherapy treatment. Our preliminary findings indicate that PBR-28 goes to areas of the brain consistent with the tumor location. Additional studies will further define whether PBR-28 detects immunotherapy-related inflammation specifically.

  • Maxwell Cooper

    Cleveland Clinic, Cleveland, OH

     

    Project title:

    "Targeting Myeloid-derived suppressor cells to inhibit immune suppression of the tumor microenvironment in glioblastoma"

    Summary:

    A promising area of brain tumor research has been investigating the interaction between glioblastoma (GBM) and the immune system. The focus of my project was defining mechanisms used by GBM to suppress the immune system’s ability to fight tumor cells. We investigated a specific protein found on the surface of GBM cells that is known to suppress the immune response. We found the glioma stem cells have higher levels of this protein than non-stem glioma cells. Our hope is to utilize this research to find new targets for drug therapies that will enable the immune system to target and kill GBM tumor cells.

  • Ramita Dewan

    National Institutes of Health, Bethesda, MD

     

    Project title:

    "High throughput genomic analysis of vestibular schwannomas in neurofibromatosis type 2"

    Summary:

    Neurofibromatosis type 2 (NF2) is a heritable syndrome that can lead to the development of numerous different tumors involving the brain and spinal cord, as well as in or along peripheral nerves. The most common tumor associated with NF2 is bilateral vestibular schwannomas, tumors which grow along the vestibular nerve in the internal ear canal. For this project, we optimized a protocol for and extracted both DNA and RNA from 82 NF2-associated vestibular schwannomas, and analyzed the quality of each sample in preparation for high resolution DNA sequencing. Our project aims to analyze the genetic changes observed in DNA extracted from this set of NF2-associated vestibular schwannomas, and identify any genes or molecular pathways which may be more prone to accumulating these changes and would thus be ideal therapeutic targets.

  • Patrick Flanigan

    University of California, San Francisco, 
San Francisco, CA


     

    Project title:

    "Role of monocyte chemotactic protein-1 upregulation in anti-angiogenic therapy resistance"

    Summary:

    Glioblastoma is a devastating brain cancer for which new therapeutic approaches are desperately needed. Antiangiogenic therapy targets tumor blood vessels in attempts to decrease tumoral nutrient/oxygen supply, but unfortunately, most glioblastomas become resistant to this therapy. Tumors that have become resistant are found to have increased macrophages (a type of immune cell) compared to before treatment, although the functional significance of this increase in macrophages isn’t well understood. In this project we found that bevacizumab-resistant glioma cells activated macrophages to the M2 state, which help the tumors grow, rather than attack them. We also identified a molecule that is decreased in bevacizumab-resistant tumors compared to sensitive tumors. The presence of this molecule in bevacizumab-sensitive tumors caused activation of macrophages to the M1 state, which fight the tumor. Going forward, we plan to investigate the efficacy of combination therapies that cut the tumoral blood supply while driving activation of macrophages to the M1 (therapeutic) state in order to improve outcomes for glioblastoma patients.

  • Michael Hadler

    University of North Carolina at Chapel Hill, Chapel Hill, NC

     

    Project title:

    "Whole kinome glioblastoma"

    Summary:

    The Cancer Genome Atlas (TCGA) has identified the incidence of mutations in glioblastoma (GBM) and lower-grade gliomas (LGG) and used comprehensive molecular analysis to show that these tumors can be grouped into multiple subtypes which have different clinical outcomes. These subtypes have different mutational profiles, notably in kinase (molecules in cells that carry out cell functions such as growth and movement) signaling pathways. However, the effects of mutations in kinases has only be studied for a few specific ones and clinical trials using individual kinase inhibitors has not improved clinical outcomes for glioma patients. The aim of my project was to uncover the array of differences in kinase mutations among gliomas and further define subtypes using multiplex-inhibitor bead coupled with mass spectrometry (MIB-MS). Starting with eight glioma cell lines, we identified 262 of the 493 known human kinases in the glioma cells. We also found that 4 of these cell lines, when combined, represent all the kinases in glioma and can be used as reference samples for future studies. Future studies will apply this technique to roughly 50 human glioma samples to learn more about kinase protein expression in glioma.

  • Jaeho Hwang

    Dana Farber Cancer Institute, Boston, MA

     

    Project title:

    "Somatic Genetic Biomarkers of Bevacizumab Response in Glioblastoma Multiforme"

    Summary:

    Glioblastoma Multiforme (GBM) is the most common and malignant primary brain tumor in humans. Unfortunately, it remains almost uniformly fatal. Despite standard treatment involving respective surgery, radiation therapy, and temozolomide, recurrence of GBM is inevitable, and patients with recurrent GBMs have limited treatment options. In 2009, bevacizumab was approved for the standard treatment of recurrent GBM. Bevacizumab (BEV) is an anti-angiogenic monoclonal antibody that acts as a Vascular Endothelial Growth Factor (VEGF) inhibitor. In this project, genetic data from 119 Glioblastoma Multiforme patients were assessed and correlated to outcomes following BEV treatment. Gene mutations in IDH1, BLM, and PRKDC were shown to be associated with longer therapeutic effects of BEV, while those of TP53, PTEN, EGFR, ERCC5, and SF3B1 were associated with less effect of BEV. Additionally, the chromosomal arms 2p and 2q were significantly amplified (extra copy(s) of all the genes in these regions of the DNA) in patients whose disease was progressing at the first follow-up exam after starting BEV, while 19p was amplified in those who exhibited partial response. Our goal is to be able to use these and any genetic marker identified in future studies to predict which patients will benefit most and which will not respond to BEV treatment.

  • Tyler Lazaro

    Massachusetts General Hospital
, Boston, MA

     

    Project title:

    "Identification of Therapeutic Targets in Posterior Skull Base Meningiomas"

    Summary:

    The goal of my project was to characterize the genetic profiles of meningiomas of the skull base to develop targeted treatments. Our preliminary data were promising for meningiomas of the frontal skull base, so this study focused on tumors of the rear part of the skull. We found that many of these tumors have mutations in genes, such as AKT1, that have been successfully targeted in other cancers. We are still discovering new ways to identify meningiomas with these clinically relevant mutations by molecular and imaging techniques. Ultimately, we would like to be able to treat these tumors without surgery, using information from their unique genetic profile.

  • Jacob Miller

    Cleveland Clinic, Cleveland, OH

     

    Project title:

    "Quality of Life Benefit after Gamma Knife Radiosurgery for Metastatic Brain Cancer"

    Summary:

    Surgery, radiation therapy, and chemotherapy have significantly extended the lifespan of patients with brain metastases over the past three decades. Recently, high doses of radiation delivered in a single session (radiosurgery) have replaced surgery and whole-brain radiation therapy for many patients. However, the quality of life benefit of radiosurgery has rarely been studied despite many trials investigating its impact upon traditional clinical outcomes. In this study, we evaluated clinical and quality of life outcomes following radiosurgery for 67 patients with brain metastases. We observed that more than 75% of patients experienced quality of life preservation through 12 months of follow-up after radiosurgery. However, patients with more than three brain metastases were at risk for earlier quality of life deterioration. These data highlight the importance of quality of life in this population, and for discussing interventions that can optimally manage symptoms, minimize side effects, and maximize cognition.

  • Panayiotis Pelargos

    David Geffen School of Medicine at UCLA, Los Angeles, CA

     

    Project title:

    "Targeting Epithelial Membrane Protein 2 for the Treatment of GBM"

    Summary:

    Epithelial membrane protein 2 (EMP2) is a protein expressed on the surface of glioblastoma (GBM) cancer cells but not on normal brain cells. In our research, we developed antibodies that specifically target these EMP2 present on GBM cells and direct the body’s own immune system to fight the cancer cells. In our preliminary mouse models, the antibodies have shown promising results in slowing tumor growth which could lead to increased survival. Our data present an extremely novel biomarker and therapeutic target for GBM. These findings suggest that targeting EMP2 may be an effective treatment modality for GBM. Further studies are needed to fully elucidate the role of targeting EMP2 in the treatment of GBM.

  • Kristin Scheitler-Ring

    University of Missouri School of Medicine, Columbia, MO

     

    Project title:

    "Radiosurgery to post-operative tumor bed for metastatic carcinoma versus whole brain radiation"

    Summary:

    The treatment paradigm for brain metastases is shifting to stereotactic radiosurgery (SRS) to the tumor bed following surgical resection, in lieu of whole brain radiation therapy (WBRT). Research comparing the two treatment options with respect to survival outcomes is sparse, thereby raising concern regarding the efficacy of tumor bed SRS, despite its increasing clinical utilization. In this project, we examined clinical data from 83 patients receiving SRS (n=37) or WBRT (n=46) following surgical resection of metastatic tumors. We found that tumor bed SRS can be used effectively to treat brain metastases after surgical resection, with better early survival and without increased radiation-related adverse events. Additional studies with a larger sample set may give more insight into factors that contribute to these outcomes.

  • Aditya Sengupta

    Brigham and Women’s Hospital, Boston, MA

     

    Project title:

    "Improving Antibody Delivery through the Blood-Brain Barrier to target the glioblastoma tumor microenvironment"

    Summary:

    Glioblastomas (GBMs) represent the most common and aggressive primary brain tumors with a median survival in adults of just one year after diagnosis. There is an inherent difficulty in delivering drugs and antibodies to the glioma microenvironment due to the presence of the blood-brain barrier, which is designed to protect the brain against toxins. Thus, in terms of therapy, the blood brain barrier has always been a hurdle for targeting drugs to brain tumors since these drugs do not cross over in adequate amounts. We sought to modify a recently developed antibody that inhibits a glioblastoma-specific protein to more efficiently deliver anti-tumor molecules past the blood-brain barrier. We have developed our molecule of interest and are currently testing its efficacy in glioblastoma models.

  • Nickpreet Singh

    University of Pennsylvania, Philadelphia, PA

     

    Project title:

    "Diffusion Indices to Measure Neurocognitive and Neurological Function Before and Subsequent to Glioma Resection: Neuroplasticity and Brain Repair"

    Summary:

    The long-term objective of the Penn Brain Tumor Center is to use new technologies and advanced neuroimaging, such as diffusion tractography and connectomics, to quantify changes in nerve fiber tracts that are the “wiring diagram” of the brain. The goal of this project was to contribute to the development of automated tractography and develop powerful new tools that can link neurological function to structure. Gliomas, for example, not only produce edema in the surrounding brain but also invade the white matter tracts (bundles of “wires” extending from neurons), in contrast to brain metastases, which do not invade along white matter. Therefore, a comparison of patients with brain metastases and glioblastomas provided an immediate application of the diffusion tractography technology. The diffusion indices proved to be a sensitive, practical, and reproducible marker of the differences in edema produced by brain metastases in comparison with that of glioblastoma. Further studies can help elaborate if these markers can also help characterize differences in infiltration between GBMs and if this can be used as a potential prognostic marker of disease progression, neurotoxicity, response to therapy, and brain repair.

  • Adela Wu

    Johns Hopkins University School of Medicine, 
Baltimore, MD


     

    Project title:

    "Elucidating the Mechanism of anti-PD-1 and BVH-4157 in Prolonging Survival in a Murine Glioblastoma Model"

    Summary:

    Glioblastoma (GBM) is the most common primary brain tumor in adults, with a median survival of 14 months. Recently, research has centered on the role of the immune system in combating GBM’s progression. PD-1 is an immune checkpoint molecule on immune cells, which cancer cells take advantage of to shield themselves from the immune system. Anti-PD-1 therapy breaks down this shield, stimulating the immune cells to attack the tumor. Anti-PD-1 therapy has improved survival and benefited patients with different cancers, including GBM. Another new area of research is the role of glutamate, an abundant neurotransmitter in the brain, in glioma survival. It has been shown that glutamate receptors are expressed on glioma and stimulate cell death of tumor cells. My project investigated the survival effect of an anti-PD1 antibody combined with a glutamate receptor inhibitor, BVH-4157. We found that each treatment, independently and in combination, prolonged survival in mice. Additionally, we determined optimal dosing for using these two treatments in combination, resulting in prolonged survival over either therapy alone.

Discovery Grants (July 2015-June 2016)

  • Amanda Garner, PhD

    University of Michigan, Ann Arbor, MI

     

    Project title:

    "Targeting the elF4E-4E-BP1 Protein-Protein Interaction for the Treatment of Malignant Brain Tumors"

    Summary:

    Glioblastoma is an incurable disease with a median survival of 12-15 months; thus, there is an urgent need to develop treatments for these malignant brain tumors. For our research, we focused on an exciting new therapeutic target for brain tumors, which affects the ability of the cancer cells to produce cancer-promoting proteins. We used this target to develop technology which can be used to rapidly discover and analyze drug-like small molecules and peptides that can alter the activity of our target molecule. Additionally, we furthered our understanding of the biology of this target in the context of glioblastoma. We plan to use our new technology to screen more than 200,000 small molecules to identify potential new drugs that will act on our target molecule. This technology can also be applied to other molecular targets in glioblastoma and other cancers.

  • Milan Makale, PhD

    University of California, San Diego, La Jolla, CA

     

    Project title:

    "Antibody-Drug Conjugates as a Novel Approach to Treat Glioblastoma"

    Summary:

    Glioblastoma (GBM) is a highly aggressive cancer associated with very poor survival even with current treatments. New, game-changing treatments are necessary to deal with this therapeutic challenge. Antibody-drug conjugates (ADCs) are demonstrating great promise as anti-cancer agents in early studies. An ADC is made of a binding antibody that recognizes tumors and is attached to a toxin, which in turn kills cancer cells. In our study, we have developed an antibody that targets a protein called prostate specific membrane antigen (PSMA), expressed on tumor blood vessels, but not normal blood vessels. Our studies showed high expression of PSMA on GBM tumor blood vessels. Our ADC is called PSMA-ADC and is designed to treat GBM. We have promising data that PSMA-ADC inhibited patient-derived GBM tumor cell growth in culture and in mouse models, and entered mouse brain tumors and killed the tumor cells. The ADC was lethal to the tumor cells, it overcame their natural resistance which is always a stumbling block, and the mice tolerated this treatment well. This exciting data has led to serious discussions with several drug companies to test PSMA-ADC in human brain tumor patients.

  • Braden McFarland, PhD

    University of Alabama at Birmingham, Birmingham, AL

     

    Project title:

    "Exploiting Therapeutic Macrophages to Enhance Standard of Care in Glioblastoma"

    Summary:

    Glioblastoma (GBM), a particularly devastating type of brain tumor, remains a challenging and difficult cancer to treat. There are many types of cells in a GBM tumor, including tumor cells, tumor stem cells, immune cells, blood vessels, and other cells, which makes developing therapies a challenge. Macrophages are a type of immune cell found in GBM tumors. In fact, macrophages can make up to 30% of the entire tumor mass. Depending on the stimuli, macrophages are activated to an M1 (therapeutic) or M2 (toxic) state. It is generally thought that in the tumor, macrophages become activated to the toxic M2 state and aid in tumor growth through the secretion of various proteins. We are trying to promote therapeutic macrophages that fight the tumor, instead of the toxic macrophages that help the tumor grow. Excitingly, we have generated a mouse model of GBM in which the macrophages help fight the tumor - M1 (therapeutic) macrophage. These macrophages attack the tumor cells and actually help the mice live longer and result in smaller tumors. My hypothesis is that therapeutic M1 macrophages will collaborate and enhance standard of care (temozolomide and radiation) in GBM. Additionally, we would like to test our therapeutic macrophage model with additional therapies for patients with GBM to determine if more optimal combinations of therapies are possible.

  • Andrew Venteicher, MD, PhD

    Massachusetts General Hospital, Charlestown, MA

     

    Project title:

    "New diagnostic and therapeutic approaches in IDH1-mutant glioma propagating cells through single-cell transcriptome sequencing"

    Summary:

    Treatment of human gliomas has been a formidable challenge due to the enormous differences between and within individual tumors. This variation lies at the heart of treatment resistance and glioma recurrence. Using state-of-the-art technologies, we are able to capture gene expression from thousands of individual cells from each tumor isolated from consented patients. We are able to detect multiple distinct subpopulations of tumor cells, including a rarer subpopulation that shares important attributes of cancer stem cells. This work will identify new potential therapeutic strategies targeting vulnerabilities in glioma stem cells specifically.  We are now expanding our large-scale single-cell RNA sequencing analysis to other primary brain tumors in children and adults. We are using both the technologies used in this work as well as newer technologies for higher-throughput analysis. We are most excited to keep pushing the forefront of single cell analysis with the newest technologies to better understand primary brain tumors.

  • Jennifer Yu, MD, PhD

    Cleveland Clinic, Cleveland, OH

     

    Project title:

    "Inhibition of Sema3C/PlexinD1/Rac1 Signaling Axis to Target Glioma Stem Cells"

    Summary:

    Glioblastoma is the most malignant primary brain tumor. A subpopulation of tumor cells, glioma stem cells (GSCs), promote disease progression and resistance to therapy. Identification of novel GSC targets is urgently needed. We have found that GSCs secrete a protein Sema3C and also have high levels of its binding partner on the cell membrane to facilitate tumor progression. With the support of this grant, we found that Sema3C signaling can activate a fundamental stem cell program. As normal brain cells do not use this signaling pathway, anti-Sema3C therapies may have a high therapeutic index. Future studies will provide proof-of-principle that targeting this pathway will improve treatment for patients with glioblastoma.

Basic Research Fellowship (2014-2016)

  • Leila Akkari, PhD

    Memorial Sloan Kettering Cancer Center, New York, NY

     

    Project title:

    "Combining Targeting of Tumor-Associated Macrophages/Microglia and Radiotherapy in Gliomas"

    Summary:

    Poor prognosis in glioblastoma (GBM) is mainly due to tumor recurrence. Macrophages are an immune cell type that when found in and around a GBM tumor, are associated with poor patient prognosis and treatment response. We investigated the kinetics of tumor associated macrophage (TAM) response following radiotherapy and whether combining macrophage-targeted therapy can improve therapeutic efficacy. We established that TAM targeting blocks radiation-induced recurrence of GBM and that combining radiation with TAM-targeted therapy leads to a more efficient and rapid regression of high-grade gliomas. Thus, we showed that targeting macrophages reduces their ability to promote recurrence. We continue to build upon this work and focus on the factors of the tumor microenvironment (the components of the tumor that are non-cancer cells) that are required for treatment resistance.

  • Véronique Frattini, PhD

    Columbia University Medical Center, New York, NY

     

    Project title:

    "The Role of CTNND2 Inactivation in Mesenchymal Glioblastoma"

    Summary:

    The goal of this project was to understand how inactivation of the ctnnd2 gene contributes to mesenchymal glioblastoma, the most aggressive subtype. We had previously identified this gene as important in brain development and found mutations of this gene in mesenchymal glioblastoma. In this project we used neuronal stem cells (NSCs) and showed that loss of ctnnd2 enhanced stemness and reprogrammed the cells to a mesenchymal cell fate and impaired the ability of the NSCs to differentiate into neurons and supporting cells normall found in the brain. We also started to define a network of cell signaling molecules, whose interactions are important in determining NSC fate. We continue to investigate the functional roles of these molecules and their interactions. These ongoing studies will help us to understand the role of ctnnd2 mutations and open new therapeutic avenues for mesenchymal glioblastoma.

  • Ethel Ngen, PhD

    Johns Hopkins University, Baltimore, MD

     

    Project title:

    "Monitoring Brain Repair by Bioengineered Remyelinating Stem Cells Using CEST MRI Reporter Genes"

    Summary:

    Brain tumor therapies usually result in severe side effects, which negatively impact the quality of life of patients post treatment. Radiation therapy in particular, has been associated with irreversible neurological deficits and cognitive impairment. Regenerative medicine offers hope for these patients, by introducing stem cells which have the capability to rebuild damaged tissues. Our research findings suggest that: 1) Radiation-induced demyelination of axons (the part of a nerve cell that carries the signals) occurs prior to the onset of complete axonal damage and is a radiation-induced brain injury component that could be targeted for remyelinating stem cell therapies. 2) Transplanting glial-restricted-progenitor (stem) cells into the brains of tumor-bearing rats following radiotherapy, but before the onset of brain injury, retards the onset of brain injury and improves the survival of the rats, presumably via axonal repair. We continue to work on preclinical advances necessary to bring this therapy to brain tumor patients.

  • Ganesh Shankar, MD, PhD

    Massachusetts General Hospital, Boston, MA

     

    Project title:

    "Genomic characterization of spinal cord astrocytomas"

    Summary:

    Astrocytomas are the most common tumor directly involving the spinal cord in children. Children diagnosed with the most aggressive astrocytomas of the spinal cord have an average survival time of 16 months. To understand the origins of these tumors and to develop improved diagnostic criteria and therapeutic treatments, we characterized the genetic changes in spinal cord astrocytomas of 23 tumors obtained from three different hospitals. We found that while less aggressive spinal cord astrocytomas had changes in genes involved in cell growth pathways, the more aggressive tumors consistently had a specific mutation in a gene involved in packaging DNA called H3F3A. The drug panobinostat has been effective against cancer cell lines bearing the same H3F3A mutation, we are currently in the process of developing clinical trial protocols to treat patients with this mutation in supratentorial or spinal cord gliomas with this class of drugs. Additionally, while working on this research, I also developed a specific test for rapidly identifying key hallmark mutations in two genes that characterize gliomas and that segregate low from high grade tumors. The purpose of this method was to augment traditional analysis during surgery to definitively secure a diagnosis of glioma. This is especially useful because of the limited sample available from biopsies and to prevent the need for additional biopsies. We are expanding the new method to include the H3F3A mutation in spinal cord astrocytoma.