Outcome Reports for Funding Ending in 2017

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Medical Student Summer Fellowship (June – August 2017)

  • Melanie Babinski, DEC

    Massachusetts General Hospital

    Project title:

    "PI3K Pathway Mutations in Brain Metastases"

    Tribute:

    In memory of Theodore F. Bohnert and in honor of Traveling Vineyard

    Summary:

    Brain metastases represent an important cause of mortality among cancer patients. The median survival time after diagnosis can be as short as 3 months and is normally only up to 2 years, and approximately half of all patients who present with symptoms will pass away due to this spread to the brain. At the moment, treatment options for patients diagnosed with brain metastases are largely palliative and there are limited curative options. However, recent work has revealed information on the genetic makeup of brain metastases. In this project, targeted gene sequencing was carried out on samples from a set of 33 breast cancer patients with brain metastases. The results are still preliminary, but we found clinically actionable variants in one-third of the cohort, and saw it potentially associated with a more aggressive properties, as patients with the mutation had a shorter mean progression-free survival time. Ultimately, we aim to further characterize the genetic profiles of brain metastases so as to better treat patients with targeted therapy and offer curative options.

  • Alex Flores, BA

    University of North Carolina at Chapel Hill

    Project title:

    "Defining the Dynamic Response of Glioblastoma Kinomes to Targeted Kinase Inhibitors"

    Tribute:

    In honor of Superman Paul & His Sidekicks and Paul Hellermann

    Summary:

    Glioblastoma (GBM), the most common type of brain cancer, is also one of the most lethal cancers, with patients surviving on average only one year after diagnosis. Currently, drugs used to treat GBM are not effective at preventing relapse. That is, the cancer frequently comes back after treatment with the drugs currently available. One reason this may happen is because these drugs only stop one signaling pathway by which the cancer can grow. It has been shown that GBM is able to take alternate pathways once a drug blocks one pathway, allowing for continued growth and relapse. We proposed to map these alternate pathways by using novel analytical techniques to monitor the molecular changes that occur in GBM tumors once current drugs on the market are administered. While the mapping is on-going, our investigations over the past months revealed 1) Specific GBM tumors (based on certain gene signatures) are naturally sensitive or resistant to specific drugs used to treat them 2) Specific GBM tumors (based on certain gene signatures) have a greater propensity to develop resistance to specific drugs used to treat them. These data will serve as the necessary foundation for future investigations seeking to hone in on the specific, targetable molecular drivers of these gene signature-specific properties.

  • Lucien Rubinstein Award Winner

    Sameer Halani, MS

    Emory University

    Project title:

    "Mechanisms of risk and disease progression in isocitrate dehydrogenase mutant astrocytomas"

    Tribute:

    In honor of Susan Kramer

    Summary:

    IDH-mutant astrocytoma is a newly defined subtype of glioma and genetic alterations associated with disease progression, response to therapy, or overall survival have yet to be identified for this subtype. Using an innovative methodology, we have been able to identify key genetic alterations and molecular features and correlate them to features of advanced disease and to clinical outcomes. This methodology applies machine-learning approaches to The Cancer Genome Atlas dataset for patients with IDH-mutant astrocytomas to identify genetic alterations associated with increased mortality risk. These tumors, like others, were once thought to behave like and share features of more aggressive disease in a way other cancers do, by: 1) contrast-enhancement on magnetic resonance imaging (MRI); 2) high tumor cell density; and 3) increased tumor cell proliferation. However, our findings have shown that in fact, these tumors live 'outside the box'--these signs of advanced disease are not predictive in IDH-mutant astrocytomas. Rather, the overall genetic instability of these tumors can better predict their clinical course; that is, the more overall number of mutations these tumors have, the worse patients will do overall. While our goal is to uncover the main players that make astrocytomas so devastating, our findings may be translated into new broad-spectrum targets for treatment and hopefully improve prognosis in a newly defined, yet poorly understood disease.

  • Michelle Lin, BA

    University of Southern California, Los Angeles, CA

    Project title:

    "Microenvironmental contribution of the choroid plexus and cerebrospinal fluid in breast to brain metastases"

    Tribute:

    In Memory of Bruce and Brian Jackson

    Summary:

    Brain metastases are a significant cause of morbidity and mortality in cancer patients. Identification of novel therapeutic targets for both alleviating tumor burden and preventing initial metastases is of paramount importance. Our brains are bathed in a liquid known as cerebrospinal fluid, which cushions the brain protecting it from injury and removes toxic metabolites. This fluid is produced by the choroid plexus which forms the blood cerebrospinal barrier (BCSFB). This is a leakier interface then the notoriously impregnable blood brain barrier. Our lab proposed that the BCSFB could serve as a possible gateway for tumor cell entry into the central nervous system (CNS). We also postulated that treatment with systemic chemotherapy can alter the permeability of this BCSFB, increase the aggressiveness of exposed tumors cells, and create conditions conducive to the development of metastatic disease. We treated choroid plexus cells with chemotherapy (Cisplatin). Following treatment, we observed a decreased in tight junction markers, which usually prevent substances from passing into the brain. When tumor cells were exposed to choroid plexus cells treated with Cisplatin, we found an increase in markers associated with invasiveness. Our lab is working on identifying the signaling pathways responsible for these observed changes, as they could serve as novel therapeutic targets to prevent the initial wave of metastases.

  • Josephine Volovetz, BA

    Cleveland Clinic, Cleveland, OH

    Project title:

    "Exploring the Role of Serpin B3 as a Cancer Stem Cell Maintenance Factor"

    Tribute:

    In honor of Naomi Berkowitz

    Summary:

    Glioblastomas (GBMs) are invasive tumors with a poor prognosis; despite therapy with surgery, radiation, and chemotherapy, most patients die within 5 years. There is a need for therapies that address GBM’s resistance to treatment. Some of this resistance has been attributed to cancer stem cells (CSCs). CSCs are more invasive than non-CSCs and reside in niches that help maintain their stemness, and therefore maintain the tumor. Targeting the interaction between CSCs and their niche can provide a valuable novel therapy. Junctional adhesion molecule A (JAM-A), an adhesion molecule used by CSCs, was found to promote CSC maintenance, but its signaling pathways are not known. Studies investigating JAM-A binding partners identified SERPINB3, a protein associated with the transformation of normal epithelial cells to cancer cells. Given the oncogenic role of SERPINB3 and its binding with JAM-A, I hypothesized that SERPINB3 represents a key component of the signaling pathway in CSCs, driving GBM survival and growth. I confirmed that SERPINB3 is present in CSCs and coexpressed with JAM-A. I decreased SERPINB3 expression in CSCs and found that a stem cell marker, SOX2, also decreased. I increased SERPINB3 in CSCs and found that SOX2 transcript levels increased in response. Next I will test the effects of SERPINB3 levels on cell survival, growth, and self-renewal. This will help us gain a better understanding of how CSCs drive GBM survival and how to target them.

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.

  • Jiangbing Zhou, PhD

    Yale University

    Project title:

    "A nanotechnology platform for systemic delivery of chemotherapy to malignant gliomas"

    Tribute:

    Supported by an Anonymous Donor

    Summary:

    Malignant gliomas, the most common primary brain tumors in adults, carry a grim prognosis. Currently, there are no effective treatments for this disease. One of the major challenges to treating and studying malignant gliomas is the lack of approaches to overcoming the blood-brain barrier (BBB), the protective membrane in which the brain is encased. With the support from the ABTA, we successfully developed a tiny drug delivery packet (nanoparticle) that can penetrate the BBB, and deliver cargo agents into brain tumors. We anticipate that this packet can be utilized as a platform to deliver therapeutics to the brain for treatment of patients with brain tumors, or research materials to the brain for studying the pathogenesis of brain cancer in animals.

Basic Research Fellowship (2015-2017)

  • Sampurna Chatterjee, PhD

    Massachusetts General Hospital

    Project title:

    "Improving immunotherapy of glioblastoma by enhancing vascular normalization"

    Tribute:

    Humor to Fight the Tumor Event Committee

    Summary:

    My research is focused on the role of the immune system in brain tumor biology. In this project, we demonstrated that current treatments for glioblastoma that inhibit the formation of new blood vessels can be improved by normalizing the tumor blood vessels and altering the macrophages (a type of white blood cell) that infiltrate the tumor. My ongoing studies include trying to modulate the immune system of the body to recognize and kill tumor cells leading to improved tumor shrinkage without the morbid toxic side effects that occur in pediatric cancer such as medulloblastoma. My ultimate aim is to improve the quality of survivorship in our cancer patients by bringing this new non-toxic therapy regimen into the clinic as fast as possible.

  • 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.

  • Richard Phillips, MD, PhD

    Memorial Sloan Kettering/Rockefeller University

    Project title:

    "Mechanisms of oncogenesis in histone-H3 mutant pediatric glioblastoma"

    Tribute:

    In honor of Bruce and Brian Jackson

    Summary:

    Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain tumors in children and currently we have no drugs which are able to effectively treat this disease. In previous work in the lab, we identified a novel drug which showed impressive effectiveness in new experimental models of DIPG, generating excitement that this drug might represent a new form of therapy patients with DIPG. Notably however because the drug was not designed for use in DIPG it was unknown exactly how the drug kills glioma cells. In order to potentially use this drug in a clinical trial, we needed to understand how the drug worked. The main goal of the project was to understand how this drug worked. Through a number of different forms of analysis, we made the unexpected discovery that the drug interferes with cholesterol metabolism. Cholesterol is required by cancer cells to grow, and the drug we studied tricks the cells into thinking they contain ‘too much’ cholesterol, and so they get rid of cholesterol. We also showed the drug works in a different way to existing cholesterol-lowering drugs. To our knowledge, this is the first demonstration that interfering with cholesterol pathways may be a therapeutic strategy in DIPG and opens the door for further analysis of these types of approaches in this disease.

  • 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.