ABTA RESEARCH COLLABORATION GRANTS
Justin Lathia, PhD and Joshua Rubin, MD, PhD
Identifying sex differences in intrinsic and extrinsic mechanisms in GBM
Advances in medicine emerge from prospective clinical trials, which allow patients with a given disease and meeting specific eligibility criteria to access studies that provide a controlled assessment of a therapy. This eligibility practice, while controlled, has largely ignored the possibility that female and male patients with glioblastoma, a highly malignant form of brain cancer, differ in incidence rates and outcome. In the present era of Precision Medicine, sex of the patient, which is linked to incidence and survival, is not used to personalize care for glioblastoma. Our preliminary and published studies uncovered a remarkably better response to standard care in female glioblastoma patients than in male patients as well as sex-specific differences in signaling networks and interactions in the tumor microenvironment. In this project, we will utilize animal models that allow us to distinguish between the contribution of sex hormones and that of sex chromosomes to determine changes in signaling pathways and alterations in microenvironmental interactions by using a real-time in vivo imaging platform. Our studies will demonstrate a paradigm for sex-specific approaches to personalized medicine in glioblastoma. Progress in our studies will establish a model approach for future studies that take into account sex as a biological variable in cancer care.
BASIC RESEARCH FELLOWSHIPS
Javier Ganz, PhD
Precancer Mutations in Normal Brain: Implications for Oncogenesis and Diagnosis
Understanding how brain cancer starts requires studying the brains of normal people, and trying to figure out where and how the earliest mutations arise that might lead to cancer years later. Our preliminary data suggest that young healthy people already harbor cells in their brain showing mutations that we know drive brain cancer. How do these early mutations arise? Such somatic mutations can be acquired during prenatal development or later in life, but are usually not inherited from the parents. Acquisition of these mutations by normal cells can lead to microscopic abnormalities starting years before detectable tumors appear. By studying the occurrence of early cancer mutations in normal brains, we will establish a roadmap of early-occurring processes that precedes cancer initiation. Brain tumors in general are derived mostly from glial cells, astrocytes and oligodendrocytes, but not neurons. We developed a method that, for the first time, is able to study the complete genome of glial cells and see how they accumulate somatic mutations, starting from fetal life and through older stages. By studying this at the single cell level, will give us a unique opportunity to obtain information with unprecedented resolution, no attainable by any other means. This research will be the first of its kind, improving our understanding of brain tumor initiation but also in providing the basis for developing sensitive methods for detecting incipient tumors where no manifestation is evident.
Albert Kim, MD
Noninvasive tools to study brain metastasis resistance to immunotherapy
Brain metastases (BM) are the most common tumor within the brain and carry a poor prognosis due to limitations in current treatment options. This is a critical unmet need, as the incidence of BM is rising as treatment for systemic cancer improves. Recent promising studies demonstrate that immune checkpoint inhibitors (ICI) can induce objective intracranial response. This response is unpredictable and often not durable. Further compounding this conundrum is the difficulty in accurately assessing response, as an increase in contrast enhancement on standard post-contrast MRI can be seen in treatment-related changes and true tumor progression. These challenges highlight the need for noninvasive biomarkers that reflect the biological response to ICI, as it is not feasible to obtain serial brain biopsies to understand why some patients benefit and others do not. Here, we leverage two novel, complementary approaches – perfusion MRI and circulating tumor DNA from blood and CSF – to understand the longitudinal changes within the tumor environment as a result of ICI. Our proposal is an unprecedented opportunity specifically tailored to patients with BM in which we will obtain detailed tumor blood vessel changes and the genomic basis for such changes during treatment. We seek to identify reasons why ICI ultimately fail, and specific patterns that predict response to ICI. This will result in optimization and better patient selection for these promising treatments.
Thi Thu Trang Nguyen, PhD
LXR Agonists combined with BH3-mimetics as a Novel Treatment for Glioblastoma
Glioblastoma is the most common primary brain tumor with a current life expectancy of 12-15 months. In this proposal, the applicants propose a novel treatment strategy for glioblastoma. Using preclinical models, the investigators are evaluating a combination therapy of two clinically validated drug compounds, BH3-mimetics as well as a certain class of cholesterol lowering compounds that were recently shown to be efficacious in model systems of GBM. We are studying the mechanism by which this drug combination works, which has informed and led us to the proposed strategy. Using the most advanced model system resembling human disease, we will be studying this drug combination in “patient-derived xenograft” model systems. The results of these studies will allow us to propose clinical studies, involving this novel drug combination. In this context, it is noteworthy that both compounds have already entered clinical testing, enabling quicker access to patient application.
Jan Remsik, PharmD, PhD
Immunological determinants of metastatic colonization of leptomeninges
Leptomeningeal metastasis (LM) or spread of cancer cells into the spinal fluid is increasingly common and results in rapid neurologic disability and death. Colonization of leptomeningeal space by cancer cells can take years or even decades after primary cancer diagnosis. The molecular basis of this process remains virtually unknown. Working from our observations from patient samples and unique experimental mouse models, we will dissect the mechanism of cancer cell entry to the spinal fluid using cutting-edge technologies. Moreover, the presence of fully functional immune system in our novel syngeneic mouse models enables us to target immune pathways essential for development and progression of LM. Our approach will rationalize the application of immune therapies, employing the patient’s own immunity as an active weapon against disseminated cancer cells.
Anh Tran, PhD
Tissue factor as a regulator of receptor tyrosine kinases in glioblastoma
Glioblastoma (GBM) is an aggressive form of brain cancer with no cure and few treatment options. Increased activation of receptor tyrosine kinases (RTKs), especially epidermal growth factor receptor, (EGFR) has been well-characterized in GBM. However, drugs that only targeting RTKs have limited efficacy on GBM patients. Our preliminary data show that tissue factor (TF), a protein normally involved in blood clotting, is increased in GBM and can activate many RTKs, even with RTK inhibitor treatment. TF does this through another protein called protease-activated receptor 2 (PAR2), and we found that we could block TF and PAR2 with drugs to decrease GBM malignancy. Furthermore, blocking these proteins also suppress brain tumor-initiating cells, which were known to cause therapeutic resistance and recurrence in GBM. In this study, we will: 1. Investigate how TF and PAR2 interact with and activate RTKs, with the goal to understand how they can help GBM tumors to evade treatments. 2. Determine how TF and PAR2 promote brain tumor initiating cells and test if this effect could be blocked by getting rid of either protein. We will also find the connection between TF, PAR2, RTKs, and tumor-initiating cells. This research will reveal novel targets for GBM therapy and extend our knowledge on the regulation of different factors that contribute GBM malignancy.
Maria Garcia Fabiani, PhD
Impact of H3G34R mutation in reprogramming the glioma immune microenvironment
This project relates to a sub-type of pediatric malignant glioma (pHGG) that is currently incurable. This tumor is found predominantly in the adolescent population and patients have a median survival of 18 months post diagnosis. The extrapolation of tested chemotherapeutics and targeted agents from adult HGG failed to improve the clinical outcome in the pediatric population, so the availability of a reliable experimental model is imperative for the testing of new therapies specifically designed for this type of tumor. The experiments proposed will shed light on many aspects of the tumor’s biology. We are interested in studying: 1) the role that the immune system plays in tumor progression and malignancy 2) and how we could harness it to test therapeutic modalities. To achieve this, we have developed a pHGG mouse model that mirrors the human disease and is a valuable tool to complete the proposed experiments. Having a mouse model to study this disease will allow us to explore many aspects of this type of tumor and possible therapies. The lab where I work has a strong background in brain cancer research and immune-therapeutics of cancer and offers an extraordinary working environment that will allow me to unravel key aspects of this tumor which currently remain unknown. We expect to provide compelling evidence to gain new insights on the biology of this subtype of pHGG which will lead to the development of novel immune-mediated targeted therapies.
Yiping He, PhD
Repurposing Remyelination Drugs for Oligodendroglioma Therapeutics
Oligodendrogliomas (ODs) begin as low grade tumors, but uniformly progress to become high grade, aggressive cancers. We aim to devise a non-toxic approach to mitigate such a progression. OD cells originate from progenitor (immature) cells of oligodendrocytes. Our study has revealed that in ~50% of OD patients, tumor cells display features of abnormal immature cells, which undergo uncontrolled proliferation (i.e., tumor progression). This is in contrast to normal cells that differentiate to become non-proliferative, functional oligodendrocytes. Coincidently, in Multiple Sclerosis (MS), defective differentiation of immature cells is a barrier to effective remyelination. As a result, extensive research has been conducted aiming to achieve therapeutic remyelination via promoting such immature oligodendrocytes to differentiate into functional, myelinating cells. Taking advantage of available therapeutic agents developed for this purpose, we have identified agents that can induce OD cells to differentiate. Among them, the most intriguing is Clemastine, an allergy relief medicine. The therapeutic efficacy of Clemastine has been proven in MS patients. We will devise a regimen for inducing OD cell differentiation, using Clemastine as a prototypic drug. The project will potentially lead to a novel treatment for ODs by repurposing commonly used, low toxicity medicines.
Wen Jiang, MD, PhD
Bridging innate and adaptive GBM immunity via phagocytosis checkpoint blockade
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. The current treatment paradigm is ineffective and carries significant toxic side effects. Increasingly, there is a growing of harnessing the power of the immune system to fight GBM. Our body’s immune system is composed of two main branches. The adaptive branch generates immune memory to prevent disease recurrence after an initial exposure. Adaptive immune cells usually stay dormant but become “activated” in the event of an ”attack”. In contrast, cells of the innate immune system are always on high alert. They are the first defenders of any pathogenic infection or malignant transformation. However, cancers such as GBM has developed the ability to escape from both branches of the immune system, which allows them to grow, spread and disrupt critical biological functions within the body. The goal of the present study is to eliminate GBM by developing a novel bispecific antibody that simultaneously blocks two molecules highly expressed in GBM and responsible for its immune evasiveness. We will: 1) Characterize the bispecific antibody’s ability to generate anti-GBM immune responses. 2) To investigate whether restoration of innate immune surveillance can boost the power of the entire immune system to eliminate GBM. Successful completion of the study would provide strong rationale for translating the bispecific antibody construct for future clinical trials in GBM.
Christine O’Connor, PhD
Cytomegalovirus oncomodulation of the glioblastoma tumor environment
Glioblastoma (GBM) accounts for ~80% of malignant gliomas annually in the US. GBM patient prognosis is poor, and even with treatment, survival is a dismal 12-15 months. This is partly due to the cancer stem cells (CSCs) within the tumor that are refractive to treatments, allowing these cells to continually expand and the tumor to regrow. Thus, novel therapies and a better understanding of the GBM tumor environment are necessary. Emerging data suggests the role for a human herpesvi¬rus, human cytomegalovirus (HCMV), in promoting the acceleration of these tumors. However, the exact mechanism(s) by which HCMV alters the GBM tumor environment remains unknown. The HCMV-encoded G-protein coupled receptor (GPCR), US28, activates many cellular signaling pathways that contribute to GBM progres¬sion. Our findings show US28 drives GBM cells towards the CSC phenotype, thus expanding the population of cells that promote tumor regrowth and recurrence. The goal of our proposal is to gain a better understanding as to how US28 modulates the GBM tumor environ¬ment. US28 is an attractive therapeutic target, as over 2/3rd of FDA-approved drugs target GPCRs. Thus, successful completion of this project will reveal US28-mediated pathways that promote tumor growth, thereby allowing us to leverage cur¬rently approved therapies to prevent GBM CSC expansion. This would prove a novel, paradigm-shifting approach to treating GBM, thus improving patient well-being and outcomes.
Min Tang-Schomer, PhD
Microcircuit Platform to Screen Ion Channel Blockers for Medulloblastoma
Medulloblastoma (MB) is the most common malignant brain tumor in children. The tumors are often subdivided into four groups that define treatment and prognosis. Groups 3 and 4 are the most likely to recur after treatment and patients with these types have the worst outcomes. Our collaborator recently used computational techniques to identify FDA-approved drugs that could be repurposed to treat these malicious tumors. They identified digoxin as a likely candidate and confirmed its antitumor activity in mouse models of MB. However, the mechanism behind digoxin’s tumor killing activity is unclear. Digoxin blocks important ion pumps in cells and may have broad effects on cell viability. Therefore, a better understanding of its mechanism of action is needed before it can be seriously considered as a potential treatment for MB. In this proposal, we will use a novel cell culture system to grow medulloblastoma cells from patients and apply electrical currents to the cells to activate ion channels. We will then apply digoxin and 5 other ion channel blockers to the cultures and monitor mechanisms by which they effect tumor cell growth. These drugs are chosen base on their ability to enter the brain from the bloodstream, their specificity for neurons, and their safety (based on FDA-approval). Therefore, we anticipate that the results from these experiments will be the first step toward identifying new treatments for this devastating pediatric cancer.
Lee Wong, PhD
An investigation of telomere maintenance mechanism in ATRX mutant gliomas
Telomeres are the stretches of DNA that protect our chromosomes. Each time a human cell divides, its telomeres become progressively shorter. Eventually, they reach a ‘crisis point’ where the cells stop growing. I will investigate how mutations in ATRX and H3.3 (2 key regulators of telomeres) activate an aberrant telomere-maintenance mechanism in brain cancers to evade the telomere crisis and cell death. This study will identify molecular targets that might be vulnerable to therapeutic interventions in brain cancers.
Zeng-jie Yang, MD, PhD
NeuroD1 dictates tumor cell differentiation in medulloblastoma
Medulloblastoma (MB) is the most common malignant brain tumor in children. Improved strategies to treat MB are urgently needed. “Differentiation therapy” represents a promising approach for tumor treatment, by means of inducing tumor cells to undergo maturation, thereby inhibiting tumor growth. Differentiation therapy is more selective to target tumor cells with less toxicity compared with conventional chemotherapy or radiation regimen. Here we propose to investigate the mechanism for MB cell differentiation, which will provide compelling evidence to support MB treatment by induction of tumor cell differentiation.
MEDICAL STUDENT SUMMER FELLOWSHIPS
Project: Synaptogenic Glioma Cell Enrichment in High Connectivity Regions of Adult Glioma
Previous research has shown that gliomas disrupt communication between nerve cells in the brain and cause the loss of brain function. Recently, Dr. Shawn L. Hervey-Jumper of the UCSF Brain Tumor Research Center identified glioma cells that have the ability to make connections with healthy neurons, called synaptogenic glioma (SG) cells
Synaptogenic glioma (SG) cells
are a specific type of cell within a glioma tumor that helps to establish connections between nerve cells.
Preliminary data from the Hervey-Jumper lab indicates that the presence of SG cells in a tumor may increase a patient’s chances of recovering from tumor-induced aphasia, or the inability to understand or produce speech.
In my previous work in the Hervey-Jumper lab, I used cutting-edge neuroimaging technology to measure neuronal activity and found glioma subtypes support neuronal communication in different ways. In my ABTA Medical Student Summer Fellowship project, I found genes that are important for glioma-neuron communication using samples from glioma patients to identify the SG cells.
- SG cells divide more frequently than other glioma cells, causing faster tumor growth.
- SG cells can enhance communication among hippocampal neurons, (brain cells that are important for memory, learning, and emotion).
This study is the first of its kind to examine the impact of synaptogenic glioma cells on functional communication in the brain.
Sakibul Huq, BS
Project: Identification of EZH2 and elf4E as New Therapeutic Targets in Chordoma
Chordoma is a rare, aggressive cancer of the skull base and spine that often goes undetected until it has reached an advanced stage. Despite extensive efforts from the scientific community, little is known about the underlying biology of chordoma, and there are currently no FDA-approved drugs to treat patients. Consequently, management of this cancer is notoriously challenging.
Recent research suggests that EZH2
proteins involved in central processes in many cancers may also play important roles in chordoma.
The central hypotheses for this project are:
- The amount of EZH2 and eIF4E in a patient’s chordoma correlates with patient prognosis.
- Targeting EZH2 and eIF4E with drugs may provide a strong therapeutic response in chordoma.
We have begun testing these hypotheses through a series of exciting experiments using human chordoma cells in culture. We have also established an animal model in which chordoma tumors are currently growing in mice. We are testing the effects of drugs that target EZH2 and eIF4E on a number of cellular processes and cell death. We are diligently optimizing the conditions in which to carry out our experiments in order to determine the impact of targeting these two proteins. We remain optimistic that this work may provide evidence for new treatment options for patients with this rare and debilitating cancer.
Rushikesh Joshi, BS
Project: Identifying Mediators of Perivascular Invasion in Glioblastoma
The poor prognosis of glioblastoma (GBM) is largely due to GBM cells spreading into healthy brain tissue, which makes complete surgical removal impossible. This invasion inevitably leads to tumor recurrence, typically within two centimeters of the initial diagnosis location. This cancer is thus able to invade critical areas of the brain and disrupt essential functions.
Using biopsies taken from various regions of the same GBM tumors, the Aghi Lab has found that there is a difference between the GBM cells that comprise the tumor core, and the GBM cells on the edge of the tumor that are invading healthy brain tissue.
We hypothesize that the increased presentation of cell surface molecules such as integrins in invasive cells bolsters their capacity to invade healthy tissue, specifically by traveling along the blood vessels of the brain.
To date, our research has shown that a protein called Extra Domain A (EDA), a variant of the standard fibronectin protein, along with three integrins (a5, aV, and B1), are increased in invasive cells. We created cells that block the expression of these molecules, to understand their invasive effects. To conduct our studies, we used a novel 3D model to mimic the structure of GBM tumors and analyze cells as they spread along the model.
By better understanding the elements that make GBM such an invasive tumor, we hope to identify specific factors, such as integrins, that can be targeted with drugs to suppress malignant invasion and improve patient survival.
Shoeb Lallani, BS
Project: Defining a Role for the GCH1/BH4 pathway in Brain Tumor Therapeutic Resistance
Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. One of the reasons GBM is hard to treat is due to the presence of a subset of cells called cancer stem cells that are able to survive chemo- and radiotherapy.
Our lab is working to determine the signals that are active in these cancer stem cells and possible ways to target these cells for new treatments.
We have identified one pathway that we think is particularly important involving a protein called GTP cyclohydrolase I. Patient data show that higher levels of proteins in this pathway correlate with poor patient survival. We also noticed higher levels of some of these proteins in brain tumor cells when they were exposed to low-oxygen conditions. Low oxygen is known to increase resistance to chemo- and radiotherapy, so we plan to determine the level of these proteins in low oxygen and correlate the levels with tumor grade and patient survival.
Learning more about the properties of cancer stem cells will help in designing better treatment options for GBM patients.
Melanie Schweitzer, BS
Project: Notch-Targeted Therapy for Choroid Plexus Carcinoma
Choroid plexus (CP) tumors are primary brain tumors predominantly found in young children and infants. There are two types of CP tumors:
- CP papilloma: A benign type of choroid plexus that has an excellent prognosis when removed through surgery
- CP carcinoma: A highly lethal type of choroid plexus that is poorly understood and has few treatment options available
In order to study CP carcinomas, we created genetic mouse models that develop CP papillomas and CP carcinoma-like tumors, which have helped us to define and understand the characteristics of the tumor cells. In this application, we will further develop the CP carcinoma mouse model to:
- Determine if the tumor characteristics we discovered are a weakness in CP tumors that can be targeted with therapy
- Test a novel small molecule drug in our model to block CP carcinoma growth.
Successful completion of these studies will help to propel these findings into clinical trials for patients with CP carcinoma.