Research Funding & Impact
The ABTA has contributed over $37 million to brain tumor research since we began funding research in 1974.
2024 ABTA-Funded Research Projects
Guided by our mission, and advised by a multidisciplinary team of experts, the ABTA is dedicated to funding research that has the potential to change the lives of people affected by brain tumors. We also aim to “seed the field” with promising up-and-coming researchers in the brain tumor space.
The ABTA awarded $1,158,000 in grants to 25 new projects
- 1 Special Project Grant
- 2 Research Collaboration Grants
- 9 Discovery Grants
- 2 Basic Research Fellowships
- 11 Medical Student Summer Fellowships
The 2024 funded projects span multiple tumor types
- Glioblastomas
- Astrocytomas & Oligodendrogliomas
- Meningiomas
- Brain Metastasis
- Choroid Plexus Carcinoma
- Brain Stem Gliomas
Research areas of focus
- Immunology/Immunotherapy
- Drug Therapies/Experimental Design
- Epigenetics
- DNA Damage/Repair Mechanisms
- Biomarkers
- Invasion/Motility
2024 Newly Awarded Grants
Special Project Grant Supported by the Flexible Research Fund
The Flexible Research Fund supports independent researchers to conduct innovative projects focused on specific gap areas in brain tumor research funding.
Milan Chheda, MD
Institution: Washington University School of Medicine
Tribute: Supported by Humor to Fight the Tumor
Glioblastoma is an aggressive brain tumor, whose incidence dramatically increases with age. We will focus on understanding the relationship between ageing and brain tumors. Instead of focusing on the tumor cells, we are testing whether the ageing brain itself may support the development or growth of brain tumors. If we find that features of the ageing brain contribute to brain tumors, this will mean that we could develop therapies that target the effects of ageing in the brain. In doing so, we may be able to prevent brain tumors or better treat them once they develop. This high-risk/high-reward study will allow us to test this idea in small studies that will inform whether this avenue of research will be helpful in treating or preventing glioblastoma in the future. The study of risk factors for developing glioblastoma is an ongoing research field with limited evidence on what drives glioblastoma development and progression. Therefore, results from this study will shed light on the ageing brain risk factors that could improve disease prevention.
Jack & Fay Netchin Medical Student Summer Fellowship
A Medical Student Summer Fellowship is a three month, mentor-guided summer research experience, intended to motivate talented medical students to pursue a career in neuro-oncology research.
Lucy Chen, AB
Institution: Johns Hopkins University School of Medicine
Mentor: Karisa Schreck, MD, PhD
Tribute: In honor of Paul Fabbri
Gliomas are a group of tumors that come from the supporting cells in the brain. They can be deadly cancers, and most gliomas are incurable. Some can be treated with drugs targeted against certain cancer-causing mutations. One such mutation found in gliomas is in the protein BRAF. This mutation causes the protein to send signals telling cells to grow and divide out of control. Currently, there are several FDA-approved drugs that target mutated BRAF and how it affects other cells. However, cancer cells eventually become resistant to these targeted therapies and continue to grow.
Previous studies have found gliomas become resistant to BRAF-targeted therapies by changing their expression of specific genes. However, no studies have been able to find a group of genes whose use can predict whether a glioma will be resistant. Here, we identified gene sets that are expressed at different levels in pediatric low-grade glioma with different types of BRAF mutations. We found that some of these gene sets are associated with better survival. In the future, we plan to test whether these gene sets can be used to predict resistance to BRAF-targeted therapies in all types of glioma.
Harrsha Congivaram, BS
Institution: Northwestern University Feinberg School of Medicine
Mentor: Feng Yue, PhD
Tribute: Fully supported by BrainUp
Based on microscope cellular imaging, meningiomas are classified into three groups with different degrees of risk for poor outcomes. While the classification system has improved clinical decision-making, a significant number of cases that are classified as “low-risk” can recur. Recent classification efforts using DNA methylation (DNAm), an adjustment to the DNA that can affect how a gene is expressed, showed improved predictive capabilities with better associations for malignancy and recurrence. However, these algorithms were developed using different DNAm platforms and methodologies, making it challenging to adopt such approaches in a clinical setting. As such, we analyzed over 1800 meningioma methylation profiles from 4 institutions and combined them into a single dataset. Further analysis of this data revealed six potential clusters representing sub-groups of the three original groups. We show that these sub-groups are predictive of clinical outcomes in a way that explains differences in outcomes within the original grouping system. Furthermore, we developed classifiers for our proposed six-group system and the original three-group system that are aware of technical variability between DNAm protocols. These classifiers will be made publicly available on a web-based platform. Furthermore, we have derived specific molecular signatures for sub-groups and signatures that directly correlate with poor prognosis. These signatures will be further assessed for potential therapeutic benefit.
Karenna Groff, MEng
Institution: New York University Grossman School of Medicine
Mentor: Dimitris Placantonakis, MD, PhD
Tribute: Fully Supported by the Southeastern Brain Tumor Foundation
Glioblastoma (GBM) is the most common and lethal brain malignancy, with a median survival of only 14-16 months after current treatment options. Recent attempts to control tumors with various forms of immunotherapy have also failed. The reason behind GBM’s resistance to new therapies is complex and not fully understood. However, GBM stem-like cells (GSCs), cells that can allow for tumors to grow back, have been shown to play a fundamental role in treatment resistance.
Based upon this insight, we identified a therapeutic target: a cell surface receptor, called CD97, that supports the growth of GSCs, and is present in GBM cells but not in healthy brain tissue. We have developed a drug to target this receptor and selectively kill GBM cells. Our research showed that, by directly injecting this drug into the tumors of mice with GBM, we can slow tumor growth and prolong survival. Additionally, injecting multiple doses of the drug further improves survival in mice compared to a single dose.
These results are promising and suggest that this drug may offer an effective therapeutic option for GBM. Our next steps will focus upon evaluating and reducing the systemic toxicity of the drug and then working to safely transition this work from the lab bench to the bedside.
Joseph Inger, BS
Institution: Brown University
Mentor: Sean Lawler, PhD
Tribute: Fully supported by the Gladiator Project
Glioblastoma, a particularly vicious brain cancer, is sadly incurable. While current treatments, such as temozolomide and tumor resection, provide some help, they often fall short. This study investigates a promising new approach that could change treatment for glioblastoma patients. VU6010572 is an investigational medication originally developed for mental health conditions that has special properties allowing it to easily cross into the brain and decrease the activity of a signaling protein called mGluR3. We believe the increased activity of mGluR3 plays a crucial role in glioblastoma’s ability to resist temozolomide, thus making it a great target for VU6010572. The combination of these two drugs could be significantly more effective than either one alone. Unfortunately, the conditions in our tests did not demonstrate the expected combined effects. We considered that the cancer cells we used might not have enough mGluR3 or that high levels of glutamate in the cell culture might interfere with the drug’s effectiveness. To address these issues, we are now exploring use of more clinically relevant patient derived cell lines and using advanced 3D brain tissue models to better mimic the brain’s natural environment potentially providing better insights into how these two medications work together.
Jill Jones, BS
Institution: Boston Children’s Hospital
Mentor: Maria Lehtinen, PhD
Tribute: In memory of Rose Digangi
The choroid plexus is the area in the brain that helps make cerebrospinal fluid. Brain cancer of the choroid plexus is called choroid plexus carcinoma. These tumors are usually seen in very young children (infants and toddlers) and have a very poor prognosis. One of the major reasons for this poor prognosis is that choroid plexus carcinoma tumors have many extra blood vessels that are not normal. These are dangerous to cut through during surgery to remove the cancer. This is unfortunate because taking out the cancer in a surgery is the only hope that patients usually have for a cure. I am motivated to figure out why and how extra blood vessels grow in choroid plexus carcinoma versus healthy tissue. In my research this summer, I used special imaging technologies and molecular biology techniques to begin answering this question. Encouragingly, I confirmed expression of a promising target that may drive pathologic blood vessel growth. In future work, my goal is to validate therapies against this target so that we can decrease bad blood vessel growth in choroid plexus carcinoma, and more young patients with this disease can live long and healthy lives. I am fortunate to share this mission with the American Brain Tumor Association (ABTA) and am humbled by the funding that the ABTA provided, in memory of Rose Digangi, to support this work this summer.
Seth Meade, BSE
Institution: Cleveland Clinic
Mentor: Jennifer Yu, MD, PhD
Tribute: In honor of Debbi Schaubman
Glioblastoma (GBM) is the most aggressive type of brain cancer, and it often grows back after treatment, making it difficult to manage. Our study is focused on investigating how electrical activity at the edge of the tumor during surgery might help us predict where the tumor will return and alter our care plan either in surgery or after surgery. By using specialized tools to measure the brain’s electrical signals in areas surrounding the tumor, we hope to identify regions that are more likely to see tumor regrowth. We are also studying the role of inflammation in this process to see if it contributes to tumor progression.
So far, we have recruited three patients for our clinical trial and have begun collecting data. Early findings are promising, showing that areas of high electrical activity near the tumor border may be associated with future tumor growth, but more data is still needed to confirm this. This information could potentially be used to improve the precision of surgeries and radiation treatments, helping doctors target areas of the brain that are at risk of recurrence. Ultimately, we aim to develop better strategies for treating glioblastoma, allowing patients to live longer while maintaining brain function.
Jonathan Mitchell, BS
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. New treatments like immune checkpoint inhibitors, which help the immune system attack cancer, have worked in other cancers but not in GBM. Research suggests that specific immune cells in the brain, called tumor-associated macrophages (TAMs), prevent the immune system from fighting GBM effectively. Additionally, GBM affects men and women differently. This project explores a protein called C1q, which is part of the immune system and is found at high levels in GBM. High levels of C1q are linked to worse outcomes, especially in females.
Our research found that removing C1q in female mice with GBM improved survival, suggesting that C1q helps the tumor evade the immune system, particularly in females. To further understand this, we studied the role of C1q in TAMs. We discovered that female mice lacking C1q had immune cells that were more active compared to those with normal C1q levels. This difference was not observed in male mice, indicating a sex-specific role of C1q in GBM. Our findings suggest that targeting C1q could enhance immune responses against GBM, particularly in women, potentially leading to better therapies and improved survival rates for GBM patients.
Megan Parker, BS
Institution:
Mentor: Chetan Bettegowda, MD, PhD
Tribute: In honor of Debbi Schaubman
Gliomas are the most common type of malignant tumors that originate in the brain. To diagnose and characterize gliomas, pathologists examine biopsies of these tumors under the microscope. While this is currently the gold standard of diagnosis, this method is limited by a high degree of subjectivity. Accurate characterization of gliomas is imperative for guiding therapy. Incomplete or inaccurate diagnoses can result in patients requiring a second biopsy or delays in treatment.
Flow cytometry is a laboratory technique used to detect and measure characteristics of cells. This technique is well-established in the diagnosis of blood cancers. It has advantages over microscopic evaluation, including the ability to analyze more cells than can be observed under the microscope and the ability to objectively quantify key molecular factors that drive the tumor’s growth and behavior.
Our team developed a method to dissociate brain tumor tissue into single cells and analyze them using flow cytometry. By applying antibodies specific to cellular proteins, we successfully detected key molecular alterations in gliomas. We also created methods to enrich tumor cells in a sample and reduce false positives. Our method has proven to be highly sensitive, with a detection limit of 0.1%, significantly better than that of next-generation sequencing, and it may improve the characterization of samples that are otherwise non-diagnostic.
Jorge Salcedo, BS
Institution:
Mentor: Robert Prins, PhD
Our study aimed to unravel the complex immune dynamics involved in melanoma brain metastasis (MBM) progression. Using a mouse model of MBM, we investigated the role of immune checkpoint blockade (ICB) therapy and its effects on tumor growth and immune cell populations.
We found that ICB-treated metastatic models developed larger extracranial tumors, reaching a maximum volume up to tenfold higher than that of controls. We also observed higher numbers of CD8+ T cells and dendritic cells in ICB-treated intracranial-only tumors, indicating an enhanced immune response. However, this difference was not seen in the metastatic models. Additionally, we noted a trend towards higher levels of interferon (IFN) alpha/beta receptors on CD8+ T cells in ICB-treated metastatic models.
These results indicate that patterns of resistance are more pronounced in ICB-treated metastatic models, which could be due to downstream changes in IFN signaling pathways. It is possible that both ICB treatment and priming of the immune system via the extracranial tumor independently promotes migration and activation of immune cells within the tumor microenvironment. Without the ability to overcome such mechanisms of resistance, this may only lead to quicker exhaustion and depletion of said immune cells. The next steps for this project will be to probe these IFN-mediated mechanisms of resistance further so that we can better understand how to overcome them and maximize the potential of therapeutic approaches.
Ethan Schonfeld, MS
Institution:
Mentor: Michael Lim, MD
Tribute: In memory of Jeffrey Michael Tomberlin
Glioblastoma (GBM) is the most common malignant brain tumor in adults. However, the standard of care has not changed since 2005. Immunotherapies, therapies that stimulate the immune response, have revolutionized the treatment of many cancers, but have thus far not worked in GBM. The use of immunotherapy in GBM is complicated by the cancer’s adaptive resistance, suggesting the need for combining immunotherapies to overcome GBM’s immunosuppressive environment. Furthermore, previous work from our lab has demonstrated that the way we give immunotherapy matters, where giving the same therapy targeted to the lymph nodes that drain the tumor results in a much greater anti-tumor immune response than a standard injection of the same therapy. In this project we sought to combine three promising immunotherapies. We hypothesized that combining the three together can result in a synergistic effect, especially when delivered in a targeted manner to the tumor lymph nodes via a gel. Using these three combined therapies, we demonstrated improved survival of the triple combination therapy versus any one of the therapies on its own or any two combined together. Furthermore, we demonstrate that using a gel to deliver all three therapies to the lymph nodes is the optimal delivery mechanism. Lastly, we show evidence that the synergistic benefit of combining three therapies likely arises by reducing the immunosuppressive adaptive response to therapy.
2024
Lucien Rubinstein Award Recipient
Suchet Taori, BA
Institution:
Mentor: Jeremy Rich, MD
Tribute: In honor of Debbi Schaubman
Glioblastoma (GBM), the most common and lethal primary brain cancer, can evade anti-tumor immune responses. Like other cancers, GBM also exhibits a metabolic reprogramming towards lactate production, a byproduct of cellular metabolism that is important for generating energy in the cell. Cancer cells are able to use lactate to grow and spread. However, the relationship between GBM metabolism and immune evasion remains unclear. In recent years, a novel role of lactate was first described, whereby lactate regulates how certain genes are expressed through a specific modification called histone lactylation. However, little is known regarding the function and molecular regulation of lactylation in cancer. In this project, we demonstrate that lactate production in GBMs induces GBM reprogramming towards an immune-cell resistant cell-type via upregulation of ‘don’t eat me’ signals in GBM, thus preventing GBM cells from being ‘eaten’ by immune cells in cell culture models and animal models. Mechanistically, we identified key driving proteins mediating the maintenance of this modification in GBMs. Genetically or pharmacologically targeting these proteins and the lactylation pathway process with state-of-the-art immunotherapy approaches resulted in significant tumor growth suppression in cell culture models and prolonged survival in animal models. Collectively, this project links gene reprogramming, tumor metabolism, and immune cell evasion in GBM, and may provide broad benefits for GBM and other cancers.
Research Collaboration Grants
The Research Collaboration Grant is a two-year, $200,000 grant, to support interdisciplinary team science projects that combine resources to streamline accelerate progress in the brain tumor field.
Jacques Lux, PhD
Co-PI: Wen Jiang, MD, PhD
Institution: University of Texas Southwestern Medical Center
Co-PI Institution: University of Texas M.D. Anderson Cancer Center
Tribute: In honor of Joel A. Gingras
Co-PI: Wen Jiang, MD, PhD
While immunotherapies such as immune checkpoint blockade have revolutionized cancer treatments, they have not been successful clinically in extending the survival of patients with glioblastoma multiforme (GBM). This project aims to address this problem by developing a novel and clinically relevant ultrasound-guided strategy to boost the patient’s immune response against GBM. We have developed a new technology that we termed MUSIC (Microbubble-assisted Ultrasound-guided Immunotherapy of Cancer) to deliver a naturally occurring immune-boosting molecule into immune cells. We propose to further improve a second generation dual functional MUSIC (dMUSIC) system that will generate tumor-recognizing immune cells to produce durable antitumor immunity against GBM. We have reengineered microbubbles (MBs), which have been clinically used as ultrasound contrast agents for more than two decades, to carry and deliver both drug and tumor antigens to immune cells. Upon ultrasound exposure, MBs implode to open temporary holes into the targeted cells and deliver their cargo. Therefore, both drug and antigen are delivered when and where we want it by applying ultrasound on the brain tumor. As MBs are clinically approved with excellent safety profiles and ultrasound scanners are ubiquitous in hospitals, the results generated could help rapidly translate this image-guided cancer immunotherapy strategy into the clinic.
Pavithra Viswanath, PhD
Co-PI: Peng Zhang, PhD
Institution: University of California, San Francisco
Co-PI Institution: Northwestern University
Tribute: Partially supported by BrainUp
Co-PI: Wen Jiang, MD, PhD
Glioblastoma is the deadliest form of brain cancer in adults. Tumor-associated macrophages (TAMs) are natural immune cells within the tumor that actively promote tumor growth and immune evasion. Our studies indicate that, unlike normal macrophages, TAMs consume glucose to produce lactate, which alters gene expression and encourages tumor growth. Lactate then needs to be exported out of the cell to prevent an increase in acidity within the cell. We show that blocking lactate export by targeting a molecule called SLC16A3 that removes lactate, eliminates immunosuppressive tumor-associated macrophages and makes tumors more vulnerable to immunotherapy. We also find that a novel imaging technique called deuterium metabolic imaging allows us to tell whether the tumor is responding to therapy within days of treatment. Based on these findings, we will determine if SLC16A3 is an promising immunometabolic target and if deuterium metabolic imaging can be used to track treatment response in mouse models of glioblastoma. Our studies will lay the foundation for translation of this innovative therapeutic and imaging strategy to glioblastoma patients.
Basic Research Fellowship
The Basic Research Fellowship is a two-year, $100,000 grant, awarded to post-doctoral fellows who are mentored by established and nationally-recognized experts in the neuro-oncology field.
Adam Grippin, MD, PhD
Institution: University of Texas M.D. Anderson Cancer Center
Mentors: Wen Jiang, MD, PhD
Tribute: In memory of Stephanie Lee Kramer
Diffuse intrinsic pontine glioma is a uniformly fatal form of brain cancer that is resistant to all current therapies. Here, we propose a novel technique that involves transforming a type of immune cell, called macrophages, from their usual role of suppressing immune responses into aggressive cancer cell hunters. By combining the powers of nanotechnology, mRNA therapeutics, and immunotherapy, we aim to reprogram these cells directly within the body using specially engineered microscopic vesicles, which are small cellular sacs, carrying the mRNA instructions needed to destroy tumors. Unlike traditional treatments, this innovative strategy holds great promise for a broader and more lasting defense against cancer by also helping the body’s immune system recognize and respond to cancer more effectively.
Mark Youngblood, MD, PhD
Institution: Northwestern University
Mentor: Adam Sonabend, MD
Tribute: Fully supported by Tap Cancer Out
Glioblastoma is the most deadly form of brain cancer in adults, and is in need of innovative new approaches to improve patient outcomes. Minimally-invasive blood tests could provide doctors with important details about how a glioblastoma changes over time in response to therapy, ensuring that the best treatments are utilized at the right time. Immunotherapy, which harnesses the power of the human immune system to fight glioblastoma, offers a powerful new approach in treating these tumors. This project will investigate a blood-based test that tracks a patient’s response to immunotherapy in glioblastoma, aiming to identify those who will benefit from use of this treatment method. If successful, our tool will shift how therapeutic decisions are made in patients, and improve outcomes by matching each glioblastoma with the most effective treatment type.
Discovery Grant
A Discovery Grant is a one-year, $50,000 grant to support cutting-edge, innovative approaches that have the potential to change current diagnostic or treatment standards of care for either adult or pediatric brain tumors.
Toshio Hara, PhD
Institution: University of Michigan
Mentor: Pedro Lowenstein, MD, PhD
Tribute: In memory of George Surgent
Glioblastoma is the most common and lethal form of intracranial tumor. It accounts for approximately 48% of the 24,500 new cases of malignant primary brain tumors diagnosed each year in children and adults in the United States. Glioblastoma is capable of infiltrating the brain, and missing even a few cells leads to high recurrence after surgical resection. There is a major gap in our knowledge as to what is the molecular identity of such invading tumor cells. To overcome this gap in our knowledge, we use a technology called single-cell RNA sequencing to measure gene expression of individual tumor cells that invade and hide in the brain. Evidence from this approach reveals the ability of tumor cells to switch their gene expression identities, by turning them on and off, along with their location. We hypothesize that the signals sent out from their surrounding environment can be recognized by invading tumor cells and determine their identities and functions. By controlling such environmental signals, the goal of this proposal is to perturb gene expression of glioblastoma cells to disrupt their abnormal behavior. Our proposed works hope to have a major impact in providing new strategies to control invasiveness, which could lead to significantly increased recurrence-free survival of glioblastoma patients–things that are not possible with the current treatment.
Tanner Johanns, MD, PhD
Institution: Washington University in St. Louis
Tribute: Fully supported by an Anonymous Family Foundation
Glioblastoma is the most common and deadliest brain tumor in adults; therefore new, effective treatment options are needed to improve outcomes for patients diagnosed with this disease. Immunotherapies are treatments that aim to improve the patient’s own immune response against cancer cells and offer many ways in which the immune system can be activated. However, immunotherapies to date have not been effective in patients with glioblastoma, and it is not clear why. We have recently observed that the most common cancer-fighting immune cell, called a CD8 T cell, expresses an enzyme called granzyme K. Not much is known about granzyme K or the CD8 T cells that express granzyme K, but the high prevalence of these cells suggests they may play an important role. Unfortunately, there are no mouse models available that allow us to perform in-depth studies to learn more about how these granzyme K cells develop, what role granzyme K or granzyme K-expressing cells play in protection against glioblastoma, or how these cells can be targeted to improve outcomes for patients with brain tumors. Successful completion of this project will result in the generation of two new mouse models that can be used to address these key questions.
Chrystian Junqueira Alves, PhD
Institution: Icahn School of Medicine at Mount Sinari
Tribute: In honor of Charles “Chip” McKinley Greenlee
Glioblastoma (GBM), the most aggressive brain tumor, is notorious for wide infiltration in the brain, making complete surgical resection impossible. Traditionally, scientists have focused on understanding the molecular factors that drive GBM migration, but how tumor cells navigate physical barriers such as confined space in the brain is not well understood. Using cutting-edge microdevices that mimic the narrow passages in the brain, we can obtain live images of how GBM cells navigate through tight spaces. Remarkably, we observed that GBM cells like to migrate through tight constrictions, illustrating the astounding ability of GBM cells to respond and adapt to physical surroundings. Here, I will dive deeper into the biomechanical flexibility behind this confined migration, by focusing on two key aspects: i) changes in the electric charge of inner membrane surface that organize the internal framework of the cells; ii) regulation of this charge by Plexin-B2, a molecule established as modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness . Functional blockade of Plexin-B2 with nanobodies will be tested to develop novel translational strategies to curb GBM invasion.
Gilbert Rahme, PhD
Institution: SUNY at Stony Brook
Mentor: Styliani-Anna E. Tsirka, PhD
Tribute: Fully supported by The Karl Schmidt Oligodendroglioma Research Fund
Diffuse gliomas are serious brain tumors with no cure. To better treat patients with diffuse gliomas, we need to understand how these tumors grow. Many diffuse gliomas start because of mutations, or changes, in a gene called IDH1. These mutations can damage special parts of the DNA structure called CTCF sites. CTCF sites act like guards, deciding how different bits of the DNA interact with each other. We’ve already found one damaged CTCF guard near a gene called PDGFRA, which is linked to tumor growth. Now, we’re looking at damaged guards near other genes to see how they might help tumors grow. Understanding how damaged CTCF guards affect tumor growth could help us find new ways to treat gliomas.
David Raleigh, MD, PhD
Institution: University of California, San Francisco
Tribute: Fully supported by An Anonymous Family Foundation
The most common brain tumor grows from the lining that surrounds the brain and is called a meningioma. These tumors are often slow growing and can often be cured with surgery, but many meningiomas require additional treatment with radiotherapy to block or slow their growth. There are no effective medical therapies to treat meningiomas that are resistant to surgery and radiotherapy. This project will study how genes influence meningioma responses to radiotherapy. Using what we have learned from studying genes in meningiomas from patients and genes in meningioma cells in our lab, we hope to find drug targets that could be used to improve treatment options and clinical outcomes for patients with meningiomas. Our studies will make use of both conventional and cutting-edge techniques that will allow us to study how each gene influences meningioma responses to radiotherapy in individual cells. These technical advances that we developed in our lab will facilitate previously impossible investigations of many dozens of genes at once, which will significantly increase our bandwidth and allow us to complete this high-risk project in the allotted year of funding. Ultimately, we hope to test the genes that are most important for radiotherapy responses in cells in this project as part of mouse studies in future projects, and then in human patients in clinical trials.
Artak Tovmasyan, PhD
Institution: Ivy Brain Tumor Center, Barrow Neurological Institute
Mentor: Nader Sanai, MD
Tribute: In memory of Brian Bouts
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival at diagnosis of 12-16 months. The current standard treatment involves maximal surgical resection followed by radiotherapy, which delays tumor progression and extends patient survival. However, the tumor always re-emerges aggressively, leading to patient death. Novel therapeutic approaches are urgently needed to enhance the tumor response to radiotherapy. Yet, developing such agents poses significant challenges, notably due to their limited ability to cross the blood-brain barrier and selectively sensitize brain tumors to radiation while sparing normal tissue. In this proposal, a novel molecule, MnP3, is proposed as a potential radio-sensitizer aimed at improving the survival outcomes for GBM patients. MnP3 is designed to overcome previous concerns regarding brain penetration and toxicity associated with earlier generation analogs by modifying specific molecular features responsible for adverse effects. MnP3 possesses significant brain targeting and improved safety profile. Our initial findings demonstrate that MnP3 enhances the sensitivity of brain tumors to radiation in animal models while protecting normal brain from radiation-induced side effects. Through this application, we intend to validate these promising preliminary results and investigate the role of the immune system in the therapeutic benefit offered by MnP3. Successful completion of this project will warrant further clinical development of MnP3 for GBM patients.
Dionysios Watson, MD, PhD
Institution: Sylvester Comprehensive Cancer Center/University of Miami
Mentor: Antonio Iavarone, MD
Tribute: Fully supported by an Anonymous Family Foundation
Glioblastoma (GBM) is the most common primary malignant brain tumor. Despite standard therapy, it invariably recurs and becomes resistant to treatment with a long-term survival of <7%. There is growing appreciation that as GBM grows, it integrates into the brain. The resulting interactions with brain cells promotes the growth, persistence, and recurrence of these tumors. However, there remains limited understanding of the mechanisms of communication between GBM and the brain. Given the universal recurrence of GBM after standard therapy, there is an urgent need to elucidate these interactions to identify novel drug targets. We previously published that GBM cells form physical connections with astrocytes, the most abundant cells that support brain function. Through these connections, cancer cells acquire astrocyte mitochondria, sub-compartments of cells which are responsible for energy production and regulation of multiple cellular processes. Astrocyte-to-GBM mitochondria transfer resulted in reprogramming of metabolism and more aggressive tumors in preclinical models of GBM. In this proposal, we interrogate the effect of mitochondria transfer on astrocyte biology, an understudied aspect of this process. We propose this as a mechanism whereby GBM in turn reprograms its microenvironment to facilitate tumor growth and persistence. Understanding this poorly studied communication pathway will identify novel therapeutic opportunities for this devastating disease.
Peng Zhang, PhD
Therapy resistance is a major challenge in treating malignant brain tumors. Loss of tumor antigen, a peptide “tag” on tumor cell surface that could be recognized by immune cells, is a strategy tumor uses to escape from being attacked by immune system, causing failure of immune response and therapy. To better understand this, we have created a brain tumor model that is highly resistant to the clinically used standard treatments, such as radiotherapy and chemotherapy. We found that these resistant tumor cells have much lower “tumor tag” level than normal tumor cells. To overcome this, we propose to develop a new mRNA therapy to enhance the tumor antigen (“tag”) presentation, making these tumor cells more visible to immune cells for a better tumor killing. To do so, we have developed a lipid nanoparticle, a fat-like sac, to protect and deliver the mRNA molecules specifically to brain tumors. By testing a library of lipid nanoparticles made by different FDA-approved lipid components, we have identified the best formulation with the highest efficiency for targeting glioma cells. As mRNA-based drug and lipid nanoparticle technology have been proved to be feasible and successful in the development of COVID-19 vaccines during the pandemic, a rapid translation of our strategy to clinical usage is anticipated. Our work may develop a new therapeutic approach to boost the body’s immune system to attack brain tumors and improve the current clinical treatments for brain tumor patients.
Julie Miller, MD, PhD
Institution: Massachusetts General Hospital
Tribute: Fully supported by An Anonymous Family Foundation
Isocitrate dehydrogenase (IDH) mutant gliomas are primary brain tumors that typically affect young and middle-aged adults. Despite treatment with radiation and chemotherapy, these tumors inevitably return, at which point effective therapies are limited. We are interested in discovering novel ways to attack IDH-mutant gliomas that are more effective and cause fewer side effects than current treatments. IDH is an important enzyme involved in metabolism, the biochemical reactions used by cells to create energy. Mutations in IDH cause changes in the way cells use nutrients and metabolites, leading to tumor formation. We believe that understanding how IDH mutations impact glioma metabolism will shed light on potential ways to take advantage of these metabolic changes to develop improved treatment strategies. In the laboratory, we recently discovered that restriction of the amino acid methionine is detrimental to IDH-mutant glioma growth. Interestingly, methionine restriction does not harm non-cancerous cells. The goal of this project is to examine methionine restriction in more detail to understand the metabolic process that are dependent on ample levels of methionine and to test if a low methionine diet can slow IDH-mutant glioma growth. By using tumor models derived from patients with gliomas, we hope our research will uncover new treatment options for IDH-mutant glioma, to eventually be tested in clinical trials.
2023 Ongoing & Recently Awarded Grants
Research Collaboration Grants
The Research Collaboration Grant is a two-year, $200,000 grant, to support interdisciplinary team science projects that combine resources to streamline accelerate progress in the brain tumor field.
Federico Gaiti, PhD
Co-PI: Gelareh Zadeh, MD, PhD, FRCSCk
Institution: University Health Network
Co-PI Institution: University of Toronto
Tribute: In memory of George Surgent
Co-PI: Gelareh Zadeh, MD, PhD, FRCSC
Tumors continuously evolve into more aggressive and treatment-resistant forms. Brain tumors, such as gliomas, illustrate the dilemma of cancer evolution. Despite standard-of-care treatments, these tumors inevitably recur, with an average survival rate of about one year, thereby underscoring an urgent need for novel treatments.
Our preliminary findings suggest that these incurable brain tumors exhibit extensive diversity within and harbor multiple types of malignant cells, presenting a significant unmet therapeutic challenge. Therefore, identifying the key molecular factors that drive this cellular diversity and promote malignant transformation is a crucial goal for neuro-oncology and represents a prime opportunity for intervention. However, we currently lack a comprehensive understanding of the primary molecular factors that contribute to glioma diversity and malignant transformation.
In this project, we aim to develop and apply innovative genomic and experimental technologies to glioma samples collected at diagnosis and upon recurrence following chemotherapy and radiotherapy. This data will enhance our understanding of aggressive malignant transformation, tumor progression, and therapeutic resistance. These studies are expected to lead to novel treatment strategies for this devastating cancer, improving patient outcomes. Additionally, this work will generate new tools for investigating tumor evolution across other types of brain tumors.
Oliver Jonas, PhD
Co-PI: Shawn Hervey-Jumper, MD
Institution: Brigham and Women’s Hospital
Co-PI Institution: University of California, San Francisco
Tribute: Partially supported by StacheStrong
Co-PI: Shawn Hervey-Jumper, MD
This project utilizes an implantable microdevice to measure multiple drug responses directly within the tumor of glioblastoma patients. We have developed a miniaturized implant, roughly the size of a grain of rice, that is implanted into the patient, remains inside the tumor for 3 days, and is then removed during a standard surgical tumor resection. The implant releases microdoses of 20 different drugs into different regions of the tumor. After surgery, we examine the tumor response to each of the treatments independently using a range of cutting-edge spatial biology techniques. This study represents the first time that measurements of multiple drug responses from inside the tumor of the same patient are realized. We expect that the resulting data set will allow us to systematically understand drug response and resistance pathways to established and novel treatment options. The goal is to rationally select highly effective combination treatment regimens that are based on each patient’s actual tumor biological response to the range of available drugs.
Derek Wainwright, PhD
Co-PI: Pilar Sanchez-Gomez, PhD
Institution: Loyola University of Chicago
Co-PI Institution: Instituto de Salud Carlos III
Tribute: Partially supported by BrainUp
Co-PI: Pilar Sanchez-Gomez, PhD
Older adults ≥65 years of age represent more than 70% of all new glioblastoma (GBM) diagnoses. Older adults with GBM tend to experience significantly worse overall survival as compared to their younger GBM patient counterparts. However, the biological underpinnings for the dismal outcomes in older GBM patients is poorly understood. Our study aims to determine how the older adult brain macroenvironment that’s, outside of the bulk GBM mass, contributes to worse outcomes in older adults with GBM . The remarkable improvements in healthcare has led to a world-wide population that is increasingly entering an age range associated with unprecedented increases in cancer incidence that will have important economic and public health consequences. Historically however, most older adults with GBM have been excluded from participating in clinical trials. Thus, more precision medicine approaches that are specifically tailored to older adults are necessary for understanding how best to improve the outcomes in this underserved GBM patient population. As direct result of our studies, we believe that our discoveries will improve treatment-related outcomes for older adults with GBM. By understanding age-dependent factors that decrease survival, we also believe that our work will indirectly improve outcomes for middle-aged and younger GBM patients that also eventually suffer from the hyper-aging effects caused by GBM.
Basic Research Fellowship
The Basic Research Fellowship is a two-year, $100,000 grant, awarded to post-doctoral fellows who are mentored by established and nationally-recognized experts in the neuro-oncology field.
Charuta Furey, MD
Institution: Barrow Neurological Institute, St. Joseph Medical Center
Mentor: Nader Sanai, MD
Tribute: In honor of Joel A. Gingras, Jr.
Glioblastoma (GBM) is the most common type of malignant brain tumor in adults and remains incurable: most patients die within two years of diagnosis. Tracking glioblastoma evolution in response to experimental therapies is crucial to developing effective treatment breakthroughs. This study proposes a new method of liquid biopsy that involves collecting cerebrospinal fluid (CSF) from a reservoir in the tumor cavity during outpatient clinic visits. This minimally invasive technique allows researchers to isolate and examine circulating tumor DNA and GBM cells over time, which can help understand how the tumor evolves and develops resistance to therapy. If successful, this study will be the first to use serial CSF biopsies to prospectively monitor GBM evolution in response to a novel DNA Damage Response inhibitor. Findings from this study will help us better understand GBM resistance mechanisms and can be leveraged to create better combination therapies. Additionally, this minimally invasive liquid biopsy technique has potential clinical utility in helping us predict treatment response, differentiate pseudoprogression, and even catch recurrent disease before traditional MRI surveillance methods.
Juyeun Lee, PhD
Glioblastoma, the most aggressive primary brain tumor, affects more men than women, and men generally have worse outcomes. These differences between men and women are due in part to how the immune system responds to the brain tumor. Immunotherapy, which aims to enhance a patient’s own immune system to fight against the tumor, has worked well in some other types of cancer, however, they haven’t been successful in treating glioblastoma. Therefore, it is important to discover a new way to improve the current therapeutics for glioblastoma patients. Our laboratory found that male and female immune cells, specifically T cells which can kill cancer cells, responded differently to the cancer, with male T cells becoming dysfunctional more quickly than female cells.
To understand why male and female T cells are different, I want to examine the cells’ energy factories, called mitochondria, and how they work differently between men and women, as mitochondria function is crucial in regulating T cell function. I hypothesize that differences in mitochondria could lead to faster T cell dysfunction (also referred to as exhaustion) and contribute to faster cancer growth in men. To investigate this further, I will study how the mitochondria in T cells behave in male and female tumors. I will also test a new treatment that could help boost the mitochondria specifically in T cells. These studies could help develop new treatments that are tailored to men and women’s different immune responses to the cancer.
Jun Nishida, PhD
Institution: Dana-Farber Cancer Institute
Mentor: Kornelia Polyak, MD, PhD
Tribute: Fully supported by Breast Cancer Research Foundation
Brain metastasis is a challenging clinical problem leading to the shortest survival among metastatic breast cancer patients, yet therapeutic options are very limited. Brain metastases of different cancers preferentially grow in specific parts of the brain. For example, brain metastases of melanoma frequently occur in the frontal regions while those of breast cancer can form everywhere but are most likely found in the back of the brain. The significance of these differences has not been studied and all patients are treated the same way regardless of the location in the brain.
The levels of nutrients in the brain are very different from those of other organs and even within the brain each region can be different. Thus, cancer cells must adapt to this special environment to be able to form tumors. In my preliminary studies I identified candidate molecules in breast cancer cells that regulate adaptation to the brain, including proteins that can be therapeutic targets. In this proposal I will further investigate how differences in nutrient levels in different parts of the brain are preferred by cancer cells with different properties and how we can exploit this to improve the treatment of patients with brain metastases. The mechanisms I identified also play a role in the growth of pediatric gliomas. Thus, the successful completion of my proposed study will facilitate the understanding and treatment of not only brain metastatic cancer patients, but also children with highly aggressive brain tumors.
Rakesh Trivedi, PhD
Institution: Mayo Clinic Arizona
Mentor: Krishna Bhat, PhD
Tribute: Fully supported by Tap Cancer Out
The most aggressive form of primary malignant brain tumor is glioblastoma, with a 5-year survival rate of less than 5%. Monitoring glioblastoma progression and treatment response with the current brain scanning methods such as magnetic resonance imaging (MRI) is extremely challenging and does not accurately reflect tumor burden. Furthermore, MRI is not a routine procedure due to the high costs involved. The alternative detection methods used in systemic cancers such as tissue biopsies are not possible in brain cancer without putting the patient’s life at risk.
This proposal aims at addressing these challenges by developing a minimally invasive liquid biopsy procedure that can be used for longitudinal monitoring of glioblastoma progression. The diagnostic power of circulating DNA released by brain tumor cells in the blood of glioblastoma patients will be evaluated using specific modifications of circulating DNA to precisely detect tumor burden. The development of such innovative, cost-effective, and safe techniques will transform glioblastoma patient management and provides a convenient way of monitoring tumor progression and treatment response. We eventually hope to develop an assay integrated with standard imaging techniques for minimally invasive monitoring of glioblastoma.
Discovery Grant
A Discovery Grant is a one-year, $50,000 grant to support cutting-edge, innovative approaches that have the potential to change current diagnostic or treatment standards of care for either adult or pediatric brain tumors.
Theresa Barberi, PhD
Institution: Johns Hopkins University School of Medicine
Mentor: Alan Friedman, MD
Tribute: In memory of Kelli McLaughlin
Glioblastoma is a highly aggressive brain cancer, with less than 5% survival at five years. NF-kB p50, or simply “p50”, is a protein whose absence renders myeloid cells, white blood cells that are part of the immune system, more inflammatory due to its inhibitory effects on genes that control inflammation. We found that immature myeloid cells (IMCs) lacking p50 are active against glioblastoma in mouse models. Once infused, these “p50-IMCs” travel to tumors, develop into mature myeloid cells, and activate other immune system cells (including T cells) to fight the cancer.
STAT6 induces anti-inflammatory genes. We expect that myeloid cells lacking both p50 and STAT6 will be even more inflammatory than cells only lacking p50 and thereby will possess an even greater ability to cure glioblastoma. We will compare the ability of IMCs lacking p50 only, STAT6 only, and cells lacking both p50 and STAT6 (called a p50/STAT6 double knockout) to eliminate glioblastoma tumors in mice. We will also monitor mice for any toxicities; we have seen none thus far with p50-IMCs. In addition, we will develop p50/STAT6 double knockout in human cells and characterize them to learn if they are suitable for use in patients.
Upon completion of these studies, we anticipate rapidly evaluating our novel p50/STAT6 double knockout immature myeloid cell immunotherapy in clinical trials with the goal of increasing rates of cure and reducing toxicities of therapy for patients with glioblastoma and other high-grade brain cancers.
Defne Bayik, PhD
Institution: Sylvester Comprehensive Cancer Center, University of Miami Health Systems
Mentor: Antonio Iavarone, MD
Tribute: Fully supported by an Anonymous Family Foundation
The crosstalk between the tumor cells and the surrounding noncancerous cells drives the aggressiveness of glioblastoma (GBM), which is the most frequent and deadly malignant brain tumor. The treatment strategies aiming to kill tumor cells have not markedly improved patient outcomes over the past few decades. Therefore, understanding the complex interactions between tumors and their environment is important for the development of more effective anti-cancer therapies. One promising strategy is to educate the immune system to fight against tumors. However, tumors employ multiple mechanisms to recruit inhibitory immune cells, such as myeloid-derived suppressor cells (MDSCs), that would support the growth of the tumors.
We previously reported that different types of MDSCs play a role in the progression of GBM in males versus females. Recently, we observed that γ-aminobutyric acid (GABA), a critical modulator of neurons, can also act as a potential regulator of female-specific MDSC activity. In this project, we aim to understand how GABA reprograms MDSCs in females, and whether we can therapeutically target the pathways activated by GABA to reverse MDSC-mediated tumor growth. This project will identify new therapeutic opportunities for GBM that account for differences between males and females. Given that several GABA pathway inhibitors are commonly used in patients with mood disorders, repurposing these drugs can have an immediate impact on GBM outcomes.
Phedias Diamandis, MD, PhD
Institution: University Health Network
Tribute: Fully supported by An Anonymous Family Foundation
Cancerous brain tumors are challenging to detect and treat partly owing to the lack of early objective patient symptoms. In other cancer types (e.g. breast/colon) early detection through active monitoring has proven effective in improving patient outcomes. These approaches are, however, difficult to implement for less common cancers like glioblastoma (the most common/aggressive brain cancer). Recently, the application of advanced analytical methods like electroencephalography (EEG), a technique that allows monitoring of the brain’s electrical activity using external scalp electrodes, has re-emerged as a powerful clinical tool to non-invasively monitor/diagnose brain disease. Similar to the use of smartwatch devices to detect abnormal heart rhythms in the general population, it may now also be possible to use the growing number of consumer-grade EEG devices, commonly used for meditation and focus, to remotely detect brain tumors earlier in their evolution. Early detection could afford more effective treatments/outcomes. Our group has begun developing software to capture and analyze EEG data directly from patients/participants’ homes. This study is to determine how feasible/reliable remote EEG data collection is and if we can detect activity changes in patients with brain tumors, as their disease evolves/progresses. If successful, this EEG-based strategy bears potential value as a remote screening tool for early detection of brain tumors, in both the at-risk/general population.
Siddharthra Mitra, PhD
Institution: University of Colorado Denver
Tribute: In memory of Katie Monson
Brain tumors are among the deadliest cancers in humans. In adult Glioblastoma Multiforme (GBM) the average survival time is 12-18 months – only 25% of glioblastoma patients survive more than one year, and only 5% of patients survive more than five years. Similarly, pediatric high-grade gliomas are among the most deadly childhood cancer, with <20% of kids living past five years of diagnosis. One way to target brain tumor cells is by using the body’s own immune system against the tumor. One of the main immune cells that you find in your body is cells called macrophages, which essentially are like scavengers that go around eating dead or dying cells, infective bacteria and cells which have been infected with viruses. Cancer cells are known to protect themselves using proteins that tell immune cells not to attack them. Previously, we have published a “don’t eat me” signal on the surface of all the tumor cells, but if you block that “don’t eat me” signal, these macrophages can eat the tumor cells.
In this proposal, we will engineer these macrophages to carry homing devices on their surface that can direct their attack specifically on tumor cells, guided by the signals on the surface of the tumor cells. CAR T cell therapy, a form of immunotherapy that uses specially altered T cells – a part of the immune system that fights diseases, including cancer involves the collection of a patient’s T cells and genetically reprogramming them in the lab to recognize markers on specific cell types in the body. Engineering a similar protein-based homing device on the surface of macrophages will give them the ability to hunt out tumors and eat them up.
Allegra Petti, PhD
Institution: Massachusetts General Hospital
Tribute: Fully supported by an Anonymous Family Foundation
Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is a devastating disease. Treatment for GBM has evolved little in recent decades, probably because this tumor type is notoriously complex: Each GBM tumor is heterogeneous with respect to genetics, tumor cell state, and immune microenvironment. In particular, a new technique called single-cell RNA-sequencing (scRNA-seq) has revealed that each GBM is a mixture of different types of tumor cells, each with different biological properties. Consequently, each tumor is essentially multiple diseases, and it will probably be necessary to treat each patient with drug combinations targeted to that individual’s tumor. Although scRNA-seq has enabled us to understand the complexity of GBM, it has not yet helped us treat the disease. This is partly because it is difficult to physically isolate and study the cell types discovered using scRNA-seq. Here, we propose a novel approach to isolating these GBM tumor cell populations, studying their therapeutic vulnerabilities, and identifying personalized drug combinations that target multiple cell populations simultaneously. Our approach is based on a new technology called CITE-seq, an extension of scRNA-seq that will enable us to define tumor cell populations and, in subsequent work, isolate them for further study using a technique called flow sorting.
Soma Sengupta, MD, PhD
Institution: University of North Carolina at Chapel Hill
Tribute: Fully supported by an Anonymous Family Foundation
In advanced cases, lung cancer that goes to the brain is a fatal disease. Treatment often uses radiosurgery, but this does not produce a durable response. We have a new drug (AM-101) that gets into the brain efficiently and can help the tumor microenvironment (the non-tumor cells and structural components in and around the tumor) become more favorable to treatments by increasing the population of an immune cell called a macrophage. What is unique is that the macrophage promoted by AM-101 kills cancer cells. We also know that AM-101 makes lung cancer cells more sensitive to radiation without side effects such as bone marrow toxicity. Once we complete these experiments, we intend to publish the data, and apply for R01 funding.
Daniel Silver, PhD
Institution: Cleveland Clinic
Mentor: Justin Lathia, PhD
Tribute: In memory of Chip Greenlee
Glioblastoma (GBM) remains among the most lethal of human cancers despite ongoing efforts to understand the mechanisms used by the tumor cells that define this cancer. The challenge is that GBM is far more than a collection of cancer cells independent from the brain. GBM invades extensively throughout the organ where it intermingles with numerous brain cells. The field has detailed several processes by which nerves and immune cells support the growth of this tumor. However, even though GBM tumors infiltrate fields of astrocytes, the most abundant cell type in the brain, we know far less about GBM-astrocyte interactions. Most mouse models of GBM develop within a capsule formed by highly reactive astrocytes. However, astrocytes do not demonstrate this wall-building behavior in human GBM. We do not understand the molecular signals that shield invasive GBM cells from astrocyte encapsulation in the human brain, nor do we fully understand the mechanisms and effects that result from GBM-astrocyte interaction. In this project, we aim to clarify the functional consequences of astrocyte-GBM interactions. Doing so will help close this major knowledge gap in the field and, more importantly, this project will produce a roster of factors that we will then evaluate as potential therapeutic targets against this devastating cancer. More generally, emphasizing astrocyte-tumor interactivity and revealing the signals that govern this relationship will help shift our perspective towards a more complete understanding of GBM as a disease of the brain, not simply a disease that resides in the brain.
Elizabeth Sweeney, PhD
Institution: The George Washington University
Mentor: Conrad Russell Young Cruz, MD, PhD
Tribute: In memory of Stephanie Lee Kramer
Glioblastoma (GBM) is the most commonly diagnosed brain cancer in the United States, impacting ~12,000 people per year. Despite intense standards-of-care that include surgery, radiation, and chemotherapy, the prognosis for GBM remains dismal, with a relative five-year survival rate of 7.5%. In response to the urgent need for effective therapies for patients with GBM, we are proposing a fundamentally new and personalized therapeutic approach that uses nanotechnology to train a patient’s own immune cells to recognize and kill their tumor cells. Our strategy involves applying heat to GBM cells that have been removed during surgery, which kills them in a way that can optimally engage with immune cells. Then, the heat-killed GBM cells are added to a dish containing immune cells from the same patient, which educates the immune cells to recognize the tumor cells. These immune cells are grown in the laboratory and then infused back into the patient as therapy. This platform is personalized to a patient’s own unique tumor makeup and as such, it allows the immune cells to recognize multiple potential targets (known and undiscovered) particular to a given patient. If successful, this project will lay the foundation for a new process for developing better adoptive immune cell therapies for treating brain cancer. As the nanoparticle-based platform can be applied to any cancer type, we envision its utility in developing effective therapies for additional brain and solid tumors.
Nehalkumar Thakor, PhD
Institution: The University of Lethbridge
Tribute: Partially supported by Brain Tumor Foundation of Canada
Glioblastoma (GBM) is one of the deadliest cancers with a dismal prognosis and survival rate. Frontline therapeutic agents are failing in the clinic and there is an urgent need to develop novel therapeutic intervention strategies for the treatment of patients with GBM tumors. Under the stress conditions found within tumors, the normal (canonical) process in cells of translating genetic messages (mRNA) into protein is reduced to conserve cellular energy. At the same time, the cells begin the non-canonical process of translating a subset of mRNAs to different proteins so that the cell can cope with the stress condition. This non-canonical process contributes to the resistance of cancer cells against therapeutic agents. Proteins in cells known as eIFs have been shown to regulate the early steps of non-canonical translation of mRNA to protein. We have identified a protein, eIF5B, that facilitates the translation of anti-death proteins and allows GBM cells to survive during high-stress conditions that would normally cause cell death. We propose to define the role of eIF5B in GBM cell survival, proliferation, and non-canonical translation using brain tumor-initiating cells from patients. These experiments will validate eIF5B as a therapeutic target for GBM. This proof-of-concept project will establish the preclinical rationale for targeting eIF5B for the therapeutic benefit of GBM patients.
