2024 Research Grant Recipients
The ABTA Research Program oversees the competitive, peer-reviewed grant process to ensure funding goes to the most promising brain tumor research. Once awarded, we track each project’s progress and long-term outcomes to measure impact and advance discoveries in the field.
2024 ABTA-Funded Research Projects
The ABTA awarded $1,158,000 in grants to 25 new projects
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
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.
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
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 Sinai
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.
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.