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.
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
Nyle Almeida, BS
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 neurocognitive deficitsThe 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: 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 aphasiaThe 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 will look for genes that are important for glioma-neuron communication using samples from glioma patients to identify the SG cells. I will then:
- Investigate whether SG cells divide more frequently than other glioma cells, causing faster tumor growth.
- Verify that SG cells can enhance communication among hippocampal neuronsBrain cells that are important for memory, learning, and emotion using patient cells in culture.
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
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 and eIF4E, proteinsMolecules that perform the functions of genes such as to stimulate growth or migration involved in central processes in many cancers, may also play important roles in chordoma.
- 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 will test our hypotheses through three specific aims:
- Evaluate the effects of blocking EZH2 and eIF4E in human chordoma cells in cultureCell culture refers to the removal of cells from a human, animal or plant to be further studied in a favorable controlled conditions in a laboratory.
- Measure the impact of blocking EZH2 and eIF4E on chordoma tumors grown in mice.
- Determine whether the amount of EZH2 and elF4E in each patient’s tumor correlates with their overall prognosis.
Our goal is to provide evidence for new treatment options for patients with this rare and debilitating cancer.
Rushikesh Joshi, BS
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. Invasion inevitably leads to tumor recurrence, typically within two centimeters of the initial diagnosis location. Within the primary tumor, the blood brain barrier (BBB)A border that allows some materials to cross over, but protects the brain from foreign substances in the blood that may injure the brain. is typically weaker, allowing the tumor to be more accessible to systemic chemotherapyChemotherapy that reaches the tumor through the blood stream, such as oral or i.v. chemotherapy..
However, when tumor cells invade other parts of the brain (away from the main tumor site), it becomes harder to target these cells with chemotherapy because they have invaded regions of the brain where the BBB is still intact, preventing drugs from getting through. Because of this, tumor cells have free range to invade critical areas of the brain and disrupt essential functions. Furthermore, additional surgeries exert equally devastating effects on quality of life, inhibiting subsequent treatment efforts.
- Integrins: Molecules on the surface of cells that are responsible for attaching cells to surrounding extracellularOutside the cell materials (such as blood vessels). They also communicate signals between the environment and the inside of the cell.
Using biopsies taken from various regions of the same tumor (at both the primary site and tissue the tumor cells have invaded), the Aghi lab has found greater amounts of specific integrins on the periphery where tumors are invasive. Because integrins connect cells to blood vessels, my summer project will investigate the hypothesis:
As cells move away from the tumor core, they react to cues in the environment around them that cause a transition towards perivascular invasion, which can be blocked with targeted therapy.
I will investigate this hypothesis by blocking integrin signals and by studying perivascular invasion using a 3D cell culture modelAn artificial environment where cells can grow and interact with their surroundings in all directions. 3D culture allows the cells to grow more similarly to how they would grow in the body.. In seeking a better understanding of the various elements that make GBM so invasive, we hope to find specific aspects of the tumor, such as integrins, to target with drugs to suppress malignant invasion and ultimately improve patient outcomes.
Shoeb Lallani, BS
Defining a Role for the GCH1/BH4 pathway in Brain Tumor Therapeutic Resistance
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Even after surgery, radiation and chemotherapy, the tumor typically grows back rapidly, resulting in a dismal patient prognosis.
The presence of cancer stem cells – cancer cells that have properties of normal stem (immature) cells, specifically the ability to generate any type of cancer cell found in a tumor sample – in GBM is one of the many reasons this tumor type is difficult to treat because cancer stem cells are able to survive chemotherapy and radiation treatment. Additionally, there are currently minimal ways to predict whether a brain tumor will or will not respond to specific treatments. This makes creating the best treatment plan for individual patients extremely difficult. With this project, we hope to:
- Determine whether specific biomarkers can indicate which patients will have better or worse outcome
- Better understand the ways that brain tumor cells survive and cause tumor recurrence and block the molecules involved with specific drugs to see if they kill tumor cells.
Learning more about both of these will help in designing the best treatments for individual patients.
Melanie Schweitzer, BS
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 excellent prognosis when removed though 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 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 targeted inhibitorA drug that specifically blocks on or a few cancer-driving signals in cells 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.