Outcome Reports for Funding Ending in 2017

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Discovery Grants (July 2016-June 2017)

  • Anita Bellail, PhD

    Henry Ford Health System

    Project title:

    "Development of potent SUMO1 inhibitors as New Anticancer Drugs for Glioblastoma Therapy"

    Tribute:

    In honor of Paul Fabbri

    Summary:

    Small Ubiquitin-like modifier-1 (SUMO1) is a small regulatory protein, which is over active in glioblastoma and drives tumor growth. In glioblastoma cell-based screening, we discovered the small molecule SUMO1 inhibitor, SUMO1 inhibition compound (SMIC1), and showed that SMIC1 penetrates through blood brain barrier into brain and suppresses glioblastoma in mice. To improve the potency of this inhibitor, we have designed and created related molecules through changing of SMIC1 structure and have identified more potent SUMO1 inhibitors. These compounds inhibit the growth of glioblastoma cell lines and the self-renewal of the cancer stem cells. This is one critical step in development of a new anticancer drug for glioblastoma therapy.

  • Vivian Gama, PhD

    Vanderbilt University

    Project title:

    "Targeting Mcl-1 to Disrupt Glioblastoma Stem Cells "

    Tribute:

    In honor of Joel A. Gingras, Jr.

    Summary:

    Our research shows that the Bcl-2 family of proteins has a unique function in stem cells by promoting the ability of these cells to become any cell in the body. A member of this protein family, Mcl­1, which is known for inhibiting cell death, is located in the mitochondria in stem cells. Here we find it regulates mitochondrial dynamics, independently of its ability to inhibit cell death. Inhibiting Mcl­1’s function, induces differentiation of normal stem cells causing the cells to stop dividing. In glioma stem cells, Mcl­1 inhibition increased cell division, making these cells more sensitive to chemotherapy. Additional studies are need to examine whether Mcl­1 could be a novel therapeutic target in glioblastoma.

  • Xi Huang, PhD

    The Hospital for Sick Children

    Project title:

    "Targeting potassium channel KCNB2 in high risk medulloblastoma"

    Tribute:

    Supported by an anonymous donor

    Summary:

    Medulloblastoma is the most common malignant pediatric brain tumor. As common drug targets in other diseases, ion channel proteins form tiny pores on cell surface to control the movement of ions. However, ion channel function in medulloblastoma remained underexplored. We identified a specific potassium channel that is abundantly present in medulloblastoma. Deleting this channel in mice strongly reduces tumor growth but does not overtly alter normal mouse development. We found that this potassium channel regulates a rare population of tumor-initiating cells that drive medulloblastoma growth. Our discovery is key to develop a tumor-specific therapy that spares normal tissue, to treat this devastating pediatric brain malignancy.

  • Peter LaViolette, PhD

    Medical College of Wisconsin

    Project title:

    "Brain Tumor Radiohistomics"

    Tribute:

    Supported by an anonymous donor

    Summary:

    Patients with high-grade brain tumors undergo magnetic resonance imaging (MRI) many times throughout treatment to determine whether their tumors are responding to therapy. This project took a unique radiological-pathological approach by combining this clinical imaging with donated whole brain tissue to train pattern recognition software to detect tumor cells that are not detectable by traditional MRI. The donated tissue in this case was used as an ultimate ‘answer key’ that showed us exactly where the brain tumor spread. Our technology creates predictive maps of tumor cell features that can show clinicians and scientists where pattern recognition software predicts cancer to be.

  • Martina Malatesta, PhD

    University of California, San Francisco

    Project title:

    "Long non coding RNAs (lncRNAs): a new frontier for glioma research and therapy"

    Tribute:

    In Honor of Paul Fabbri

    Summary:

    The human genome produces many thousands of long noncoding RNAs (lncRNAs), a recently discovered class of molecules in cells. It has been recently discovered that many lncRNAs play key roles in human diseases including cancer. To identify lncRNAs that are required for the growth of glioma, we conducted a CRISPR interference screen to individually block the function of thousands of lncRNAs in cells. This screen identified 65 lncRNAs whose function affected the ability of glioma cells to multiply. Extensive validation, using more robust and specific tests, has confirmed the findings from the screen. Our study provides new tools and strategies for understanding and developing lncRNAs as a large new class of therapeutic targets for the treatment of gliomas.

  • Josh Neman-Ebrahim, PhD

    University of Southern California

    Project title:

    "Role of cerebellar microenvironment in medulloblastoma development"

    Tribute:

    Supported by an anonymous donor

    Summary:

    Our goal is to understand the biology of medulloblastoma (the deadliest childhood brain tumor) in order to develop an effective treatment. During tumor development, cancer cells must evolve and adapt to their immediate environment in the brain, known as the microenvironment. The current project exploits foundations of neuroscience to advance our understanding of how microenvironmental interplay between normal brain and medulloblastoma cells leads to cancer growth and spread. Our results show tumor cells are able to take up GABA molecules, which are released by brain cells and are abundant in the brain, and use it as an energy source for growth and spread. Furthermore, by blocking GABA from being used by tumor cells, we were able to prevent tumor growth and spread.

  • Renee Read, PhD

    Emory University

    Project title:

    "A YAP/TAZ inhibitor for treatment of GBM"

    Tribute:

    Supported by an anonymous donor

    Summary:

    Glioblastomas (GBMs), the most common primary malignant brain tumors, are resistant to current therapies. Our lab uses interdisciplinary approaches to uncover cellular pathways that control GBM growth and to identify drugs that target these pathways. We found that the YAP/TAZ pathway is abnormally activated in GBMs and that a YAP/TAZ inhibitor, the drug verteporfin, blocks growth of GBM cells. Verteporfin is FDA-approved to treat eye diseases, but has not been previously tested on brain tumors. We found that verteporfin is taken up by glioblastoma tumors in mice, but not in normal brain. Ongoing investigations will test methods for improving delivery of the drug to the tumor. We seek to test the therapeutic efficacy of verteporfin in pre-clinical GBM models and to test the therapeutic potential of verteporfin in human patients.

Basic Research Fellowship (2015-2017)

  • Hernando Lopez-Bertoni, PhD

    Hugo W. Moser Research Institute at Kennedy Krieger

    Project title:

    "miRNA-based regulation of GBM propagating stem-like cells"

    Tribute:

    In honor of Joel A. Gingras, Jr.

    Summary:

    My research focuses on unearthing molecular events that drive glioblastoma (GBM) stem cells and using this knowledge to develop new ways to treat brain cancer. Our recent discoveries show that the coordinated actions of the proteins Oct4 and Sox2 create a tumor propagating stem cell-like state in GBM cells. These proteins signal for decorating the DNA with molecules that turn genes off, resulting in a decrease in the amount of a set of other signaling molecules called microRNAs (miRNAs). We further show that if we add back two specific miRNAs (miR-148a and miR-296-5p) that are repressed by Oct4/Sox2, we can efficiently block the stem cell-like behavior and the tumor propagating characteristics in the GBM cells. Our findings identify Oct4/Sox2 signaling as excellent candidates for therapeutic intervention.

  • Megan Muroski, PhD

    Northwestern University

    Project title:

    "Dual Approach to Enhance Nanoparticle based treatments of Brain Tumors"

    Tribute:

    The Bradley Benton Davis Memorial Foundation

    Summary:

    Nanoparticles are tiny packages that can be used to deliver therapy to tumors. In this project we determined that using specific small molecules, called peptides, on the nanoparticles are able to increase delivery of the therapeutics to the tumor site. Furthermore, the nanoparticles we used have magnetic properties. Therefore using a magnetic field, we are able to use the magnetic properties of the nanoparticle to destroy surrounding tumor tissue. We have gained insight to the distribution of these nanoparticles after magnetic field treatment, and have demonstrated that the particles are small enough to be cleared away from the body after treatment. This study was crucial to understanding the distribution of the nanoparticles and steps needed to better target gliomas. Future studies will examine the effects of the magnetic field device on the immune system after treatment.

  • David Raleigh, MD, PhD

    University of California, San Francisco

    Project title:

    "Investigating Gli2-mediated activation of Hedgehog target genes in medulloblastoma"

    Tribute:

    In honor of Susan Kramer

    Summary:

    More children die from brain tumors than any other type of cancer, and the most common type of brain tumor in children is medulloblastoma. Like all cancers, medulloblastoma is caused by uncontrolled cell growth. Approximately one third of all medulloblastoma cancers arise when a particular signal that tells brain cells to grow, called Hedgehog (SHH), gets stuck in the “on” position. In this study, we used human tumor samples and mouse genetic models to discover signals that cause this type of pediatric brain cancer to grow. When we used targeted drugs to block those signals in mice, we were able to prevent the growth of these tumors. Our findings suggest that a similar strategy might be effective in human patients with SHH medulloblastoma.

Medical Student Summer Fellowship (June – August 2016)

  • Abdul-Kareem Ahmed

    Brigham & Women’s Hospital/Dana-Farber Cancer Institute

    Project title:

    "Overcoming immunosuppression in the treatment of glioblastoma using gene-mediated cytotoxic immunotherapy"

    Tribute:

    In Honor of Collegiate Charities Dropping the Puck on Cancer and Joggin for Jill

    Summary:

    Glioblastoma multiforme is the most common primary malignant tumor of the central nervous system in adults, and the most lethal. Novel therapies are desperately needed. Gene-mediated cytotoxic immunotherapy (GMCI) is a treatment for tumors that essentially mimics an infection. This stimulates the immune system against the tumor. Immune checkpoint inhibition (ICI) is a separate treatment that works by decloaking tumors. This allows the immune system full access to respond to and kill tumor cells. In this project, we combined these two treatments, and tested how well they work in treating glioblastoma in mice. We found a complementary effect between these two therapies, where one increased the effectiveness of the other. Combined treatment resulted in greater survival in mice than in mice treated with either therapy alone. These findings strengthen the argument for combination therapy for glioblastoma in human clinical trials.

  • Lucien Rubinstein Award Winner

    Raymond Chang

    Weill Cornell Medical College

    Project title:

    "Synergistic Antineoplastic Activity of PI3K Inhibitor ZSTK474 and MEK inhibitor Trametinib on Diffuse Intrinsic Pontine Glioma Cells"

    Tribute:

    In Honor of Collegiate Charities Dropping the Puck on Cancer and Super Lucy

    Summary:

    Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor. Over 90% of patients die within two years of diagnosis. Current therapies, including radiation therapy and adjuvant chemotherapy, only prolong survival by a few months. Recent research has revealed promising new drug targets, but tumors may use other signaling pathways to avoid the effects of any one drug. Our work aims to target multiple molecules that can act in parallel. We have found a combination of two drugs that work synergistically to inhibit DIPG cell growth. Our next step will be to test this drug combination in an animal model of DIPG and target these treatments specifically to the tumors.

  • Patrick Flanigan

    University of California, San Francisco

    Project title:

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

    Tribute:

    In Honor of Collegiate Charities Dropping the Puck on Cancer and Race for Grace

    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.

  • Tyler Lazaro

    Massachusetts General Hospital


    Project title:

    "Identification of Therapeutic Targets in Posterior Skull Base Meningiomas"

    Tribute:

    
In Honor of Collegiate Charities Dropping the Puck on Cancer and Naomi Berkowitz

    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.

  • Adela Wu

    Johns Hopkins University School of Medicine

    Project title:

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

    Tribute:

    In Honor of Collegiate Charities Dropping the Puck on Cancer and The E-Rasers!

    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.