2018 Research Project Summaries
Home>2018 Research Project Summaries
RESEARCH COLLABORATION GRANT
Anders Persson, PhD and Andrew Chi, MD, PhD
Synthetic lethal targeting of NAD(P)H-dependent DNA damage in IDH mutant gliomas
With ~20,000 new cases diagnosed in the United States each year, gliomas are the most common malignant primary brain tumor in adults. About a third of gliomas have mutations in the isocitrate dehydrogenase (IDH) genes, specifically IDH1 or IDH2. Although patients with IDH mutations have a better prognosis, nearly all IDH mutant gliomas regrow after radiation and chemotherapy. If the tumor regrows, no therapy is effective and most patients die from their tumor. The lack of relevant IDH mutant glioma models available to study has been a roadblock in developing new therapies for IDH mutant gliomas. However, the Persson and Chi laboratories have successfully established {tooltip}cell cultures{end-texte}Artificial system to grow and study cells in a controlled environment, outside of a human or animal.{end-tooltip} and animal models using patient-derived IDH mutant gliomas. Recent studies suggest that current therapies that specifically target the IDH1 mutation may not be an effective way to control gliomas. Therefore, our laboratories have used an alternative strategy to identify vulnerabilities of IDH mutant glioma cells..- Beta-lapachone: A naturally occurring compound obtained from the bark of the lapacho tree that has cancer preventive properties and is currently tested in clinical trials
- NAD+: An important molecule involved in metabolism
- Determine whether processing of beta-lapachone by the enzyme NQO1 induce cell death of IDH1 mutant glioma cells and whether NQO1 is a biomarker for response to beta-lapachone treatment
- Identify other agents that reduce NAD+ and other drugs that work cooperatively with beta-lapachone to specifically kill IDH mutant gliomas
BASIC RESEARCH FELLOWSHIPS
Zhenyi An, PhD
Targeting TLR2 in EGFR/EGFRvIII+ glioblastoma
Glioblastoma (GBM) is the most common malignant brain tumor in adults and there is currently no cure. Increased copies of the genes named EGFR and EGFRvIII are commonly seen in GBM tumors.- About a third of GBM patients who have extra copies of EGFR also have extra copies of EGFRvIII.
- Almost all GBM tumors with EGFRvIII have extra copies of EGFR, indicating that these two molecules might work together to promote tumor growth.
- Investigate the role TLR2 has in regulating tumor growth and the types of immune cells in the tumor (using GBM patient samples, GBM cell lines and well-established GBM mouse models).
- Test if blocking TLR2 would be an effective treatment for GBMs that have increased copies of EGFR and EGFRvIII, and if blocking TLR2 can be effectively combined with immune-therapy.
Wei Du, MD, PhD
Unraveling regulatory T cell-dependent anti-tumor mechanisms in brain metastasis
The metastasis (or spreading) of cancer cells to the brain is a threatening reality for cancer patients that can result in a dismal outcome and severe neurological symptoms. Unfortunately, current therapies for brain metastases offer only minimal benefits. In order to develop new therapies for prevention and treatment, we need to further understand of how these cancer cells set up tumors in the brain. Regulatory T cells (Treg): A type of {tooltip}immune cell{end-texte}Cells found in the body that fight off infections and disease.{end-tooltip} that blocks other immune cells and can help tumor growth. In primary and metastatic tumors, a high level of Treg cells correlates with poor prognosis. While the brain has many cell types that affect metastatic tumor growth, we hypothesize that Treg cells promote brain metastasis by modifying the brain environment in a way that makes it easier for tumors to grow. This research will provide much needed knowledge about the interactions between the immune system and the cancer cells that enter the brain and form tumors. A better understanding of these interactions will lead to new therapies that are greatly needed for metastatic breast cancer and melanoma patients.Morgan Schrock, DVM, PhD
A novel antimitotic in glioblastoma
Only 3 percent of glioblastoma (GBM) patients live longer than five years, which stresses the desperate need for new therapeutic strategies.- Mitosis: the process of one cell becoming two
- Antimitotics: drugs that block mitosis
- Test this new critical role for MKlp2 in mitosis
- Determine the therapeutic potential of blocking MKlp2, in combination with standard GBM therapies
- Characterize MKlp2 expression in naturally-occurring canine cancers to determine whether treating canine brain tumors can serve as a preclinical study to testing MKlp2 inhibitors in GBM.
Euhnee Yi, PhD
Tracing extrachromosomal DNA inheritance patterns in glioblastoma using CRISPR
Glioblastoma (GBM) is the most aggressive primary brain tumor; it has poor prognosis and frequently {tooltip}recurs{end-texte}Comes back.{end-tooltip} after therapy.- Tumor heterogeneity: Substantial differences in the cells that make up a tumor, like differences in the amount types of genetic material found in different cells within a single tumor.
- Extrachromosomal DNA (ecDNA): DNA that is not part of the chromosomes
Fan Zhang, PhD
Programming tumor-clearing macrophages with targeted in situ gene therapy
Macrophages (mφs) are {tooltip}immune cells{end-texte}Cells found in the body that fight off infections and disease.{end-tooltip} that infiltrate into gliomas in high numbers. Upon reaching the tumor, they undergo a switch from an activated state, known as M1, to an {tooltip}immunosuppressive {end-texte}Blocks the normal disease-fighting functions of immune cells.{end-tooltip} state, called M2.- M1: Activated state of mφs that attack cancer cells
- M2: Immunosuppressive state of mφs that helps tumors to grow into other parts of the brain
- Provide evidence for using gene-modification systems to “correct” immune function within the tumors without resorting to treatments that broadly disrupt the immune system.
- Provide a basis for combining materials science, gene therapy, and immunology to develop new immunotherapies for the cancer treatment.
DISCOVERY GRANTS
Loic Deleyrolle, PhD
Targeting glioma slow-cycling cells using autologous dendritic cell vaccine
In the last 20 years, available therapies have done little to improve prognosis for glioblastoma patients. It has been proposed that the most important clinical target to improve disease outcome may be a specific fraction of tumor cells known as cancer stem cells.- Slow-cycling cells: Cells in a tumor that can go dormant, are resistant to traditional therapies, and have characteristics of cancer stem cells.
Christian Grommes, MD
Characterizing and modulating the immune evasion landscape in CNS Lymphoma
Primary Central Nervous System Lymphoma (PCNSL) is a rare, but highly aggressive form of non-Hodgkin lymphoma that is only found in the central nervous system. Currently, treatment options are limited to chemotherapy and radiation. New potential treatment approaches use agents – called immune checkpoint inhibitors – that utilize the patient’s own immune system to battle cancer cells. Cancer cells can “hide” from {tooltip}immune cells{end-texte}Cells found in the body that fight off infections and disease.{end-tooltip} by displaying immune checkpoint proteins. By using immune checkpoint inhibitors to block these immune checkpoint proteins, cancer cells become “visible” to the immune system and can be killed. This concept has been very successful in treating Hodgkin lymphoma; however, whether or not PCNSLs use immune checkpoint proteins to go undetected from immune cells is largely unknown. The goal of this project is to learn more about the distribution of checkpoint markers in a large set of banked PCNSL tissues. To help conserve the precious tissue samples, we will use an innovative staining system that allows us to examine multiple markers in a single sample. By studying the tissues, we will:- Be able to correlate the checkpoint protein analysis with DNA sequencing data that we already have for these tissues
- Test whether checkpoint inhibitors alter the levels of the checkpoint proteins using new models of PCNSL.
Christopher Hubert, PhD
WDR5 is a Niche-Specific Vulnerability in Glioblastoma
The cells that make up glioblastoma (GBM) – the most common and severe type of brain cancer – have a significant genetic diversity, which is part of the reason GBM treatment options remain ineffective. This diversity is due to the way that tumor {tooltip}stem cells{end-texte}Stem cells are unspecialized cells that can divide to create new copies of themselves while also creating other more specialized cell types.{end-tooltip} can give rise to other tumor cell types, as well as the great variation in the conditions around individual GBM cells.- Glioma stem cells (GSCs): Tumor cellsthat have the ability to give rise to all cell types found in a particular tumor. The characteristics of GSCs can significantly vary between patients, and a single tumor may have several different types of GSCs.
- Glioma stem cell ‘niche’: A distinct region and environment within a tumor where glioma stem cells are located. The niche helps in the maintenance of stem cell state and also plays a role in making the tumor resistant to therapies. There can be different kinds of niches harboring different types of GSCs in a single tumor.
- Explore how WDR5 drives GBM growth
- Test a specific inhibitor of WDR5 in patient-derived pre-clinical models
Matthew Sarkisian, PhD
Primary Cilia-Derived ARL13B As A Biomarker and Promoter of Gliomagenesis
Gliomas are the most common form of brain cancer and can often be deadly. This proposal will examine the impact that the protein ARL13b has on glioma growth. While little is known about ARL13b, it is known to enhance the signaling of another protein called smoothened (SMO) by preventing its breakdown and keeping it active. Patients with gliomas that have high levels of ARL13b and SMO tend to have significantly shorter survival outcomes, suggesting the interaction between these two molecules makes tumors more aggressive.- Primary cilia: Part of the glioma cell that stems out from the cell surface, like an antennae or whiskers. Primary cilia control {tooltip}signaling pathways{end-texte}A group of molecules in a cell that work together to control cell function, such as cell division or cell death.{end-tooltip} that may regulate tumor cell reproduction, migration, survival, or other cell functions.
- If ARL13b levels outside of the cells increase as tumors grow
- If disabling ARL13b inhibits glioma growth or if it potentially enhances receptiveness to SMO inhibitors (which are already in development for cancer patients).
Stephanie Seidlits, PhD
A biomaterial approach to identify mechanopathology driving glioblastoma invasion
Glioblastoma (GBM) is a highly lethal brain cancer due to its aggressively invasive nature, multi-drug resistance and inevitable recurrence.- Glioma stem cells (GSCs): A subset of GBM cells that are resistant to treatment, highly invasive and thought to cause recurrence.
- Extracellular matrix (ECM): The proteins and sugars that make up the space surrounding GSCs. The ECM assists in the migration of GSCs away from the primary tumor to other areas, where they then give rise to recurrent tumors.
- How the brain matrix drives GSC invasion
- How migrating GSCs alter their surroundings to promote tumor recurrence
- How treatment resistance affects these behaviors.
MEDICAL STUDENT SUMMER FELLOWSHIPS
Neil Almeida
Development of mass cytometry probes to assess function and phenotype of T-cells
{tooltip}Genetic variation{end-texte}Differences between cells in gene mutations or in genes that are turned on or off.{end-tooltip} among glioma cells within individual tumors is a major challenge. Immunotherapies a single antigen (a molecule that can activate an immune response) are likely to fail due to the growth of tumor cells that do not have that antigen as a result of genetic variation. In an attempt to overcome this challenge, the Okada lab at the University of California, San Francisco is currently conducting a clinical trial for low grade gliomas that using an immunotherapy directed at 10 antigens from a variety of proteins that are abundant in glioma cells. To monitor how each patient’s immune system recognizes each of the antigens, I used a cutting-edge technology called CyTOF mass cytometry that can detect and measure many different characteristics of cells at the same time. I have already developed probes called tetramers that detect {tooltip}immune responses{end-texte}When immune cells are activated to eliminate a specific target{end-tooltip} against the antigens. For this project, my goal is to apply this technology to analyze tumor and blood samples from the clinical trial patients in order to uncover the number and functionality of their immune cells. My objective will be to, for the first time, establish this technology as a method to simultaneously evaluate immune cell characteristics and the precision of the antigens.Joshua Bernstock, PhD
Immune checkpoint blockade in combination with oHSVs for pediatric brain tumors
Primary malignant central nervous system tumors are the leading cause of cancer-related death and disability in children. While advances in surgery, radiation and chemotherapy have improved the survival rates of children with malignant brain tumors, extreme mortality persists in certain {tooltip}subpopulations{end-texte}Groups of patients whose tumors have similarities.{end-tooltip} and current therapies are often associated with extreme toxicity and life-long side effects. Genetically engineered oncolytic herpes simplex viruses (oHSVs) -a modified form of the viruses that produces common cold sores- are capable of selectively targeting and killing cancer cells and, therefore, have emerged as a promising therapeutic option for pediatric patient populations. This project will attempt to identify ideal pediatric patient groups for viral and immunotherapies, and in so doing explore the roll of {tooltip}immune checkpoint inhibitors{end-texte}A type of immunotherapy that blocks the molecules that cancer cells use to hide from the immune system.{end-tooltip} in combination with oHSVs (G207 and M032), which are currently being studied in clinical trials for some types of childhood and adult brain tumors. If successful, this research will provide evidence for rapid transition into clinical trials for children with high-grade brain tumors.Saksham Gupta
Defining the Immunophenotype of Meningioma
Meningiomas are the most common primary brain tumor and can typically be completely treated with surgery. However, a small percentage of meningiomas recur and cannot be controlled with any available chemotherapies.- Immunotherapy: Treatments that use a person’s own immune system to target and fight cancer.
Casey Jarvis
Effects of Host Pericyte Deficiency on Angiogenesis in Glioblastoma
Glioblastoma (GBM) is the most common and deadly type of primary brain cancer, with 12,500 new cases diagnosed each year. Even with aggressive therapy, most patients do not survive more than a year after diagnosis. Our lab is interested in studying the factors that make glioblastoma so malignant.- Angiogenesis: The formation of new blood vessels. Angiogenesis is essential for tumor growth.
- Pericytes: {tooltip}Contractile{end-texte}Capable of contracting or causing contraction.{end-tooltip} cells that wrap around the cells that form our blood vessels to control the expanding and contracting of capillaries.
Adam Lauko
Effects of a Glioblastoma Secreted Cytokine on Myeloid-Derived Suppressor Cells
Glioblastoma (GBM) is the most common malignant brain tumor and continues to have poor prognosis, with survival averaging between 12 and 15 months. While advancements in chemotherapy and radiation have proven to be effective in other cancers, the use of these treatments has done little to increase glioblastoma survival rates. One explanation is that glioblastoma does an excellent job at shutting down the immune system at the tumor site, allowing the tumor to hide. Normally, after fighting an infection, cells known as myeloid-derived suppressor cells (MDSCs) deploy a full arsenal of proteins that shut down the immune system, preventing damage to healthy cells. We recently discovered that glioblastoma has figured out a way to hack this regulation, causing MDSCs to shut down the immune system at the tumor site, thus allowing the tumor to hide.- Macrophage migration inhibitory factor (MIF): The molecule that glioblastomas uses to activate MDSCs to shut down the immune system at the tumor site.
- Look at the signaling that occurs inside of MDSCs after MIF stimulates the cells.
- Determine which proteins in the MDSC arsenal are activated after MIF stimulation.
Gina Rhee
The contribution of stromal cell senescence to sex differences in glioblastoma
Men have a greater chance of developing brain tumors and a lower chance of survival compared to women. Additionally, the risk of brain tumors increases with age more rapidly for men than women. These patterns show that patient sex has a large influence on brain tumor formation and growth, particularly in age-associated processes. Over time, cell damage builds up in older cells, giving them the potential to transform into cancer cells. As a defense mechanism, our body “retires” these damaged cells, permanently halting their growth and division. With age, our body will gather more of these retired, or senescent, cells. Despite retirement, these cells still impact tumor formation and growth. Senescent cells release compounds that can either encourage or prevent the growth of nearby cells. In the brain, senescent cells may release different distinct compounds in men and women, which could contribute to men having a higher risk for brain tumors. While we know that senescent cells are an integral part of tumor formation, their exact role in the brain remains largely unknown. Thus, understanding this process is important as it may provide insight into new avenues for treatment. In this project, we will:- Compare different properties of this retirement process in male and female brain cells using mouse models to determine if female brain cells undergo this process more easily than male brain cells.
- Examine brain tumor growth in the presence of male senescent cells, female senescent cells, and normal brain cells.