Research Funding & Impact
ABTA-Funded Research Projects
2022 Research Funding
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 $871,000 in grants to 21 new projects
- $550,000 funded 11 Discovery Grants
- $300,000 funded 3 Basic Research Fellowships
- $21,000 funded 7 Medical Student Summer Fellowships
- The 2022 funded projects span multiple tumor types:
- Glioblastomas
- Low Grade Gliomas
- Meningiomas
- Brain Stem Gliomas
- Research areas of focus:
- Immunology/Immunotherapy
- Genetics
- Epigenetics
- Imaging
- Biomarkers
- Angiogenesis
- DNA Damage/Repair Mechanisms
The ABTA has contributed over $34.2 million to brain tumor research since we began funding research in 1976.
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.
Read summaries of the research outcomes from the 2022 summer projects featuring the
2022 Rubinstein Award Winner David Hou!
David Hou, BA
Institution: Northwestern University
Mentor: Catalina Lee-Chang, PhD
Tribute: In Honor of Paul Fabbri
Glioblastoma (GBM) is a deadly brain cancer with a current survival of only 15 months despite standard of care. We previously developed a vaccine (Bvax) using a type of immune cell, called B cells, that allows the body to use its own immune system to target GBM. We showed that Bvax can result in a very potent survival benefit in preclinical GBM models and hypothesized that an important mechanism of Bvax is to activate CD8 T cells (another type of immune cell) which can then directly kill cancers.
To study the interactions between Bvax and CD8 T cells, we developed a system in which Bvax could activate CD8 T cells in a plate. We found that Bvax could utilize a protein called IL15 to activate CD8 T cells and give them the ability to remember what the cancer cells look like. This memory T cells to attack during future encounters will tumor cells, which is vital for an optimal GBM therapy. These Bvax-activated CD8 T cells showed a strong ability to kill tumor cells in experimental settings. We also found that Bvax could change the way CD8 T cells use energy, which allows these T cells to better survive long-term in the brain and kill tumor cells. Finally, we began developing our Bvax-activated CD8 T cells into a novel therapy and found that these CD8 T cells could be transferred back into mice and would maintain their memory profile and potential ability to kill tumors in the brain.
Shreya Budhiraja, BA
Institution: Northwestern University
Mentor: Atique Ahmed, PhD
Tribute: Fully supported by BrainUp
Glioblastoma (GBM) is a form of brain cancer that affects 12,000 adults in the US every year. Treatment usually involves surgical resection, followed by radiation and chemotherapy. Unfortunately, despite such invasive treatment, the average survival is only a year after diagnosis. This poor prognosis seems to be due to GBM’s inherent aggressiveness, the reason for which remains largely unknown. To determine which genes are responsible for this aggressiveness, our lab performed a genome-wide screen in GBM cells. From this screen, we identified one gene in particular, THOC1, that was found to drive this aggressiveness; however, the mechanism by which this gene acts in GBM has never been studied before.
Our investigation into THOC1 has revealed that it prevents deadly structures called R-loops from forming on the telomeres, the ends of the DNA known to be especially protected in cancer. We specifically saw that disrupting the function of THOC1 resulted the formation of R-loops and g shorter, damaged telomeres in GBM. We also assessed whether a THOC1 inhibitor, called luteolin, could effectively promote these deadly R-loops in GBM to prolong mice survival. Indeed, we found that the combination of luteolin and the standard-of-care chemotherapy temozolomide (TMZ) was able to prolong survival mice. Overall, these findings have revealed crucial insight into a previously unknown mechanism of GBM aggression, greatly contributing to our understanding of this novel therapeutic approach to combat GBM.
Eric Chalif, BA
Institution: University of California, San Francisco
Mentor: Manish Aghi, MD, PhD
Tribute: Fully supported by Southeastern Brain Tumor Foundation
Glioblastoma (GBM) is the most aggressive primary brain tumor, and despite a standard of care for patients that includes maximal safe resection followed by chemotherapy and radiation, the prognosis is still grim. Unfortunately, new classes of medications, such as immune checkpoint inhibitors that have revolutionized treatment for cancer outside of the Central Nervous System have so far been unsuccessful in clinical trials for GBM. However, drugs that activate the immune system by other means remain particularly promising candidates for the treatment of GBM due to its ability to suppress the immune system.
These mechanisms of immunosuppression are diverse and often redundant, which makes targeting any one agent insufficient to completely overcome the suppressive state. It is likely that combinatorial therapy will be necessary in the development of successful regimens. After first creating the virus, we then validated its in vitro function by confirming viral spread, viral stability, and viral production of our target genes. We then demonstrated superior survival of our new combination virus in a mouse model of GBM in comparison to cytosine deaminase alone. These findings will enable future studies in combinatorial immunotherapy, and they signify an exciting step towards the future development and refinement of new therapeutic modalities in human clinical testing.
Stephen Frederico, MS
Institution: Children’s Hospital of Pittsburgh
Mentor: Gary Kohanbash, PhD
Tribute: In memory of Jeffrey Ragan Frost
Tumors of the brain and spinal cord are the most common cancer in children and the leading cause of cancer-related death in children. Two of the deadliest brain tumors in children are diffuse intrinsic pontine glioma (DIPG) and pediatric high-grade glioma (pHGG). Fortunately DIPG and pHGG can be safely targeted by the immune system as these tumors express foreign substances unique to the tumor known as glioma associated antigens (GAAs). T-cells which are largely considered the immune warriors of the body contain a T-cell Receptor (TCR) that can recognize and respond to GAAs enabling this cell to attack the tumor. Unfortunately however few T-cells navigate to the site of the tumor which limits the body’s ability to eliminate the disease.
In this research project, our team extracted T-cells bearing the TCR capable of responding to GAAs from brain tumor patients. We then isolated the TCR sequence and implanted this sequence in normal T-cells which enabled them to create the TCR themselves and respond to GAAs. We then confirmed the presence of this TCR on the surface of our T-cells via tetramer staining and flow cytometry. Finally, we paired our TCR bearing T-cells with tumors cells that have GAAs and found that our T-cells were able to recognize and kill the tumor cells. We now intend to grow these TCR bearing T-cells into large numbers and administer them to tumor-bearing mice in hopes of observing a survival benefit.
Kyle McGrath, BS
Institution: University of Florida
Mentor: Maryam Rahman, MD
Tribute: In memory of Brian Bouts
Glioblastoma (GBM) is a deadly brain cancer with a current survival of only 15 months despite standard of care. We previously developed a vaccine (Bvax) using a type of immune cell, called B cells, that allows the body to use its own immune system to target GBM. We showed that Bvax can result in a very potent survival benefit in preclinical GBM models and hypothesized that an important mechanism of Bvax is to activate CD8 T cells (another type of immune cell) which can then directly kill cancers.
To study the interactions between Bvax and CD8 T cells, we developed a system in which Bvax could activate CD8 T cells in a plate. We found that Bvax could utilize a protein called IL15 to activate CD8 T cells and give them the ability to remember what the cancer cells look like. This memory T cells to attack during future encounters will tumor cells, which is vital for an optimal GBM therapy. These Bvax-activated CD8 T cells showed a strong ability to kill tumor cells in experimental settings. We also found that Bvax could change the way CD8 T cells use energy, which allows these T cells to better survive long-term in the brain and kill tumor cells. Finally, we began developing our Bvax-activated CD8 T cells into a novel therapy and found that these CD8 T cells could be transferred back into mice and would maintain their memory profile and potential ability to kill tumors in the brain.
Khashayar Mozaffari, BS
Institution: University of California, Los Angeles
Mentor: Isaac Yang, MD
Tribute: Fully supported by The Gladiator Project
Despite the technological advancements in both the operating room and pharmaceuticals, the treatment options for glioblastoma remain limited and for the most part, ineffective. Glioblastomas have a lot of abnormal blood vessels; therefore, targeting the signal that result in blood vessel growth has received considerable attention and effort in the scientific community. Although there have been promising pre-clinical results, the “anti-vascularization” agents have not been effective in improving patients’ overall survival. Prior research has suggested that tumor blood vessel growth in glioblastoma is likely not dependent on just one pathway, but rather there are multiple signaling pathways that enable these tumors to receive adequate nutrition and oxygen supply for growth.
Epithelial membrane protein-2 (EMP2) is a protein that we believe is involved in some of the alternate signals for blood vessel formation in glioblastoma tumors. Through this project, we demonstrated its association with worse survival in patients, and furthermore, evaluated it in the laboratory. Using multiple cell line models, we illustrated the involvement of this protein in tumor formation, and more importantly, noted that treatment against EMP2 resulted in reduced growth of the cancer cells. Although our results need to be subsequently validated in animal models, we believe this is an important step towards finding a novel target in treating glioblastoma.
Janet Wu, BA, BM
Institution: Stanford University
Mentor: Michael Lim, MD
Tribute: In memory of Jeffrey Michael Tomberlin
Glioblastoma (GBM) is the most aggressive and deadly form of brain cancer that patients face. STING agonist drugs are treatments that help stimulate the immune system, and they present an exciting new class of immunotherapies that holds potential to induce effective antitumor immune responses. Immune cells, particularly myeloid-derived cells, are a major barrier to inducing immune responses in GBMs. With this project, we have begun to decipher the mechanisms of STING agonist drugs to oppose myeloid-induced immune suppression, specifically targeting dendritic cells (a type of myeloid immune cell).
We proposed that STING agonist drugs will increase antitumor immune responses by improving dendritic cell (a type of immune cell) function in mouse GBM models. Preliminary data have shown elevated antigen processing, an important step in immune activation, after STING agonist treatment. While we will need to refine and repeat these experiments to validate our findings, our preliminary data give us hope that STING agonist drugs may enhance patient survival and advance to clinical trials in the future.
Lastly, these antigen processing experiments are novel in the field of neuro-oncology research. To our knowledge, there have not been studies published reporting on antigen processing in glioma models, especially not after STING agonist treatment. We are hopeful that we can continue to contribute novel studies and results throughout this project as it proceeds and are extremely grateful for the support that the ABTA has provided for this summer term.
2022 Newly Awarded Grants
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.
Jorge Ibanez, PhD
Institution: St. Jude Children’s Research Hospital
Mentors: Giedre Krenciute, PhD and Susanne J. Baker, PhD
Tribute: Fully supported by Humor to Fight the Tumor
The goal of this project is to develop antigen-specific T cells as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor resistant to radiation and chemotherapy. The immune defense system against cancer often fails because cancer can evade or actively inhibits immune response. However, genetic modification of the patient’s own immune system can be used to endow T cells with the ability to recognize and kill cancer cells. Genetically engineered T cells has shown dramatic success in clinical studies against leukemia, as well as promising results against solid tumors. We have now developed this treatment approach for pediatric patients with DIPG. In our methods, we have modified T cells to recognize and kill tumor cells that specifically have a molecule called B7-H3. These modified T-cells have demonstrated anti-DIPG activity in pre-clinical models. In this project we now propose to improve B7-H3-specific T cells anti-DIPG activity, by enhancing the interaction between T cells and tumor cells. This interaction is crucial as it mediates effective and sustained T cell antitumor response. First, we will characterize molecules that control T cell and DIPG cell interaction. Then we will knock-out RASA2, a molecule that weakens T cell and DIPG interaction and test if this modification improves T cell anti-DIPG response. If our pre-clinical approach is successful and a clinical study is justified, we have the resources to develop a Phase I clinical trial at our institution.
Kristin Huntoon, PhD, DO
Institution: University of Texas M.D. Anderson Cancer Center
Mentor: Betty Kim, MD, PhD
Tribute: Fully supported by StacheStrong
Cancer cells in glioblastoma can hide from the body’s immune system, thus allowing for the cells to continue growing. These cells can hide by expressing a surface molecule that makes the cells invisible to the immune system. Other therapies designed to activate the immune system against glioblastoma have been tested in clinical trials but have failed to demonstrate significant improvement in overall survival. This failure may be due to this ability of cancer cells to evade detection due to this molecule on the cell’s surface. In the proposed project, we will preclinically test our novel therapy, which is designed to unmask the invisible cloak on glioblastoma cells, allowing immune cells to detect and destroy them. The resulting tumor cell fragments stimulate immune signaling pathways, which further amplify immune responses against glioblastoma. We will evaluate the antitumor effect of this therapy against patient glioblastoma models established in mice which have a functional human immune system, thus potentially providing us with direct evidence of the therapeutic efficacy of this new treatment. As glioblastoma is difficult to treat, the proposed project can significantly propel the field of brain cancer research forward and directly aligns with future strategies of developing more effective therapies for glioblastoma.
Aram Modrek, MD, PhD
Institution: New York University School of Medicine
Mentors: EriK Sulman, MD, PhD and Jane Skok, PhD
Tribute: Fully supported by Tap Cancer Out
Radiation therapy, like some chemotherapies, is thought to be effective at killing cancer cells because it damages the genetic material (DNA) of cancer cells within a tumor. However, the aftermath of radiation is extremely difficult to study because the damage to the DNA is random. An analogy of this would be to consider raindrops falling on a lake; we cannot predict where the next raindrop will fall, and we cannot predict how the hundreds of ripples they create may look from one moment to another. Similarly, radiation particles hit the cell’s DNA at random locations, causing a ripple effect of damage and a cascade of events in which the cancer cell repairs the damage. To circumvent the random nature of DNA damage by radiation so that we can better understand the consequences, we develop here a system that allows us to create hundreds of damaged DNA sites at the same time, and at pre-mapped locations. The preliminary data thus far has shown that using this approach allows us to study the “aftermath” of DNA damage with much greater clarity in glioblastoma than has previously been possible. For example, we can see how DNA mutations arise, and how the cell may leave chemical modifications or “scars” on the DNA that change how the DNA is interpreted by the cell. Ultimately, it is the goal of this fellowship proposal to fully develop these tools and learn more about the fundamental biology so that we may therapeutically target the aftermath of DNA damage to prevent glioblastoma from being able to recover from therapy and grow back.
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.
Osama Al-Dalahmah, MD
Institution: Columbia University
Mentor: Peter D. Canoll, MD, PhD
Tribute: Fully supported by the Uncle Kory Foundation
Glioblastoma (GBM) is a devastating malignant brain tumor that defies surgical resection and traditional therapies. Despite the advances in GBM management, patient survival is dismal because there are no effective therapies. Recent efforts examined targeting cells other than GBM cells, mainly immune cells, as a potential treatment for GBM, but this approach was ineffective. This may be due to the nature of the cells that reside in the periphery of the tumor resected by the neurosurgeon (resection margin), which consists of few tumor cells and immune cells, and many neurons and astrocytes.
Astrocytes are the major support cells in the brain that maintain the health and function of other brain cells. Evidence suggests that astrocytes contribute to GBM spread and growth. My preliminary data suggests molecules that come from astrocytes can promote GBM progression. In this study, I hypothesize that eliminating these molecules, and thereby blocking the interaction between the astrocytes and GBM cells, will lead to reduced GBM spread, increased GBM cell death, and may make GBM more vulnerable to therapy. I will test this hypothesis in animal models of GBM, patient derived GBM tissue, and cellular models of GBM using a combination of cutting-edge molecular studies designed to test GBM cell function and gene expression. My project has the potential to uncover novel therapies for GBM based on targeting astrocytes and may provide neurooncologists with additional tools to combat GBM.
Floris Barthel, MD
Institution: The Translational Genomics Research Institute
Mentor: Michael Berens, PhD
Tribute: In honor of Joel A. Gingras, Jr.
By catching glioma progression early, we can treat it faster and keep it under control. Glioma follow-up generally consists of repeated MRI-scans and physical examination. Unfortunately, by the time a new tumor is detected, the relapsed tumor already consists of billions of cells, making treatment needlessly difficult. There is thus a critical need for new techniques that can detect recurrence earlier than currently possible.
There is now immense opportunity in developing technologies capable of detecting recurrence from liquid biopsies such as from a drop of blood. The majority of DNA is stored in the nucleus of a cell and one promising strategy to predict recurrence is to search for fragments of tumor DNA circulating in the blood using DNA sequencing. Unfortunately, studies using DNA from the nucleus to predict recurrence in glioma have not been successful. However, a separate piece of DNA is stored in mitochondria, which are cellular organelles (organs of the cell) that function to provide energy. In contrast to nuclear DNA, mitochondrial DNA has a number of properties making much more likely to be detected circulating in blood. Using circulating mitochondrial DNA as a marker to track cancer burden is therefore incredibly promising. If this research is successful, it will revolutionize the care of glioma patients by translating into new technologies that can detect tumor recurrence early, effectively increasing patient lifespan and quality of life.
Andrew Beharry, PhD
Institution: University of Toronto
Mentor: Sunit Das, MD, PhD
Tribute: Partially supported by Brain Tumor Foundation of Canada
Gliomas are a classification of primary brain tumour. The standard of care often begins with surgical resection whereby the surgeon uses pre-operative scans (e.g., MRI) as a guide to identify the cancerous tissue that should be removed. However, as tissues are constantly changing, using a single diagnostic image for surgery can be challenging and so surgeons often depend on their sight and touch, which leads to uncertainty in tumour margins, causing cancerous tissue to remain post-surgery, or the removal of healthy tissue, which could be detrimental to the patient. A solution to overcome these issues is to use fluorescence guided surgery (FGS) which uses small molecules called fluorophores that target cancer cells to enhance the real-time detection of tumours during surgery. In the context of existing research and treatment, a molecule called 5-aminolevulinic acid (5-ALA) has been used for FGS but is only effective for high grade gliomas and not for guiding the resection of lower-grade, deep-seated tumors. Our project describes the development of the first fluorescent chemosensor for a mutant form of isocitrate dehydrogenase 1 found in 80% of adult low-grade gliomas. Our proposed sensor will produce red fluorescence in gliomas and yellow fluorescence in healthy tissue, thereby permitting rapid identification of gliomas over healthy tissue of patients in the operating room. If successful, clinicians around the world can routinely employ the sensor for FGS, reducing recurrences post-surgery, thereby improving patient survival rates.
Aashim Bhatia, MD
Institution: The Children’s Hospital of Philadelphia
Mentors: Timothy Roberts, PhD, and Michael Fisher, MD
Tribute: Fully supported by An Anonymous Family Foundation
Currently the standard approach of monitoring brain tumors includes radiology imaging, such as MRI. These clinical MRIs provide important information for the clinical teams but have many limitations in knowing if a cancer treatment is working. We are researching an MRI approach to looking at sodium levels in the brain and brain tumors, since we know brain tumors have increased sodium levels based on our preliminary data and the literature. However, much more data is needed and there are no research studies in children. Diffuse midline gliomas are highly aggressive brain tumors that are treated with radiation. After radiation, the goal is the tumor shrinks in size, but radiation changes can make the tumor look like it is enlarging, when actually the tumor itself is getting smaller, and we currently don’t have an easy way to determine this with clinical MRIs. Biopsy cannot be performed at multiple timepoints during treatment due to the risk of complications. We believe measuring the sodium values in tumors with this advanced imaging technique (Sodium MRI) proposed in this grant will help understand the behavior in brain tumors that cannot be obtained with the current clinical MRIs. If successful, this advanced MRI technique will make an accurate diagnosis of tumors that are responding or not responding to treatments, allowing doctors to make treatment decisions quickly to improve outcomes in children with brain tumors.
Henk De Feyter, PhD
Institution: Yale University
Tribute: In memory of George Surgent
Magnetic resonance imaging (MRI) plays a critical role in guiding treatment of patients with glioblastoma, the most aggressive and lethal brain tumor. MRI scans can provide exquisite detail about the location and shape of a brain tumor. However, from MRI scans we cannot immediately tell if a tumor is growing or not. Instead, multiple MRI scans are needed over several months, to see if a tumor is changing in size. Even this can be challenging because cancer treatments can often lead to changes on the MRI scans that appear as if a tumor is growing when in reality, it is not. This uncertainty about tumor growth makes it complicated for doctors to design the best treatment plan and can lower patients’ quality of life.
We recently developed a new MRI-based technology (deuterium metabolic imaging, DMI) that can image the fuel consumption of a brain tumor. Before DMI scans, patients are given a safe, non-radioactive form of sugar, dissolved in water that they drink. One hour later the DMI scan is performed to visualize the high sugar consumption that is typical for these aggressive tumors. This new DMI technique could make it possible to detect to what degree a tumor is still active, in a single scan.
In this project we propose to test if DMI is indeed good at detecting growing tumors in patients with glioblastoma, by comparing DMI with resected tumor tissue. Both DMI scans and tumor tissue are collected from patients that are participating in a therapeutic clinical trial. If successful, DMI will allow doctors to make informed decisions about treatments earlier in the progression of disease and will hopefully lead to better outcomes for patients.
Federico Gaiti, PhD
Institution: University Health Network
Mentor: Gelareh Zadeh, MD, PhD, FRCSC, FAANS
Tribute: In honor of Joel A. Gingras, Jr.
Tumors continuously evolve towards more aggressive and resistant forms. Brain tumors illustrate the problem of cancer evolution. Despite standard-of-care treatment, many of these tumors inevitably recur. Glioblastoma (GBM) is the most aggressive and common type of primary malignant brain tumor, with a survival rate averaging about one year. Thus, there is an urgent need for novel treatments.
Our preliminary work suggests that these incurable brain tumors display a large diversity among tumor cells both within and between tumors. Identifying the key factors that underlie this cellular diversity that leads to the conversion of normal cells to cancer cells is therefore a critical goal with broad implications for oncology. Towards this goal, we seek to apply innovative genomics and experimental technologies to unique brain tumor samples. These findings will allow us to better understand differences between individual malignant cells and identify the molecular factors that promote brain tumor cells growth and therapeutic resistance.
We envision that these factors can be exploited to devise novel treatment strategies designed to limit the evolutionary potential and growth of these lethal tumors, ultimately improving patient outcomes. We further anticipate that the approaches generated in this work will be broadly applicable to other brain tumor types, yielding novel frameworks to address the central challenge of brain tumor evolution.
Edjah Nduom, MD
Institution: Emory University
Tribute: Fully supported by Southeastern Brain Tumor Foundation
Patients suffering from glioblastoma desperately need new treatment options. We have identified a combination immunotherapy that could provide a critical breakthrough. Checkpoint inhibitors are a new type of cancer immunotherapy that has revolutionized cancer treatment. Cancer cells are smart and prevent the immune system from attacking them by stimulating “checkpoints” that tell the immune system to stand down. Checkpoint inhibitors block these immunosuppressive checkpoints and restore the ability of the immune system to attack cancer directly. Unfortunately, checkpoint inhibitor therapy has not worked well enough for patients suffering from glioblastoma. Scientists believe this is due to a population of cells called macrophages that keep active immune cells out of the tumor. A promising new treatment, OS2966, could block these macrophages and enable checkpoint inhibitors to work in glioblastoma. OS2966 has been tested in mice, and it shows activity against glioblastoma. Also, OS2966 is already being evaluated for safety in patients in a phase 1 trial for patients with recurrent glioblastoma (NCT04608812).
In this project, we will test OS2966 together with pembrolizumab, a checkpoint inhibitor that is FDA approved for other cancers. We will determine if these drugs can activate immune cells grown in dishes with glioblastoma cells. We will also treat mice with brain tumors using these immune therapy drugs. After successfully completing these studies, we will be able to rapidly bring these drugs to clinical trials for patients.
An-Chi Tien, PhD
Institution: Barrow Neurological Institute – St. Joseph Medical Center
Mentor: Nader Sanai, MD, and Shwetal Mehta, PhD
Tribute: Fully supported by An Anonymous Family Foundation
Meningiomas are the most common primary brain tumors with approximately 35,000 new cases each year in the United States. Among them, 20% of meningiomas are aggressive and there is no FDA-approved drug treatment for this population, thereby patients suffer from repeated surgical resections and radiotherapy and the long-term side effects that result from these treatments. The Ivy Brain Tumor Center has initiated a phase 0 clinical trial to investigate a promising drug, ribociclib, that aims at dampening tumor growth, one of the hallmarks of meningioma cells. While the clinical trial is showing early signs of promising clinical effect, we have identified patients that respond to the treatment for a long period of time, representing the ‘responder’ patients who stay progression-free for a median of 22 months.
In this proposal, our goal is to identify a common genetic signature in the responder patients that will help identify patients who are likely to benefit from this treatment. The signature that we identify from this study will be validated in a larger phase 2 study to develop companion diagnostic biomarkers for this drug. Furthermore, we propose to use a patient-derived meningioma mouse model to understand how meningioma cells become resistant to ribociclib in ‘non-responder’ patients and seek to strategize future combination treatment options for them.
Pavithra Viswanath, PhD
Institution: University of California, San Francisco
Mentor: Susan Chang, MD
Tribute: Fully supported by An Anonymous Family Foundation
Gliomas are a pernicious form of cancer with long-lasting physical and cognitive deficits. Mutations in the metabolic enzyme isocitrate dehydrogenase (IDHmut) are the defining molecular feature of lower-grade gliomas. Unlike many cancers, obtaining biopsies repeatedly from glioma patients is difficult because of the complications of brain surgery. As a result, management of IDHmut glioma patients is dependent on non-invasive magnetic resonance imaging (MRI) techniques. However, because MRI does not highlight biological events critical for tumor growth, it does not reliably report on disease progression and response to therapy.
Deuterium Magnetic Resonance Spectroscopy (DMRS) is a non-invasive, non-radioactive method of imaging tumor metabolic activity. Our preliminary studies provide strong evidence for the ability of a non-radioactive molecule called deuterated alpha-ketoglutarate to monitor IDHmut activity in gliomas. In this proposal, we will validate the ability of deuterated alpha-ketoglutarate to determine tumor burden and early response to therapy in preclinical IDHmut glioma models. Clinical translation of our studies is possible within 2-4 years and will provide clinicians with a novel precision imaging tool for monitoring IDHmut glioma patients.
Jacky Yeung, MD
Institution: Yale University
Mentor: Lieping Chen, MD, PhD
Tribute: Fully supported by An Anonymous Family Foundation
Meningiomas are the most common primary intracranial tumors with a prevalence of ~170,000 cases in the United States. While surgical resection is often curative for benign meningiomas, higher-grade tumors tend to recur. There is a clearly unmet need for alternative therapies. Tumor blood vessels may be a chemical and physical barrier for effector T cells (a type of immune cell) to reach and attack the tumors. Recently, our group identified a novel interaction between CD93, and its binding partner IGFBP7 two molecules that are found in high levels in tumor blood vessels but not normal blood vessels. We can target the interaction between these two molecules to improve drug delivery and increase immune cell infiltration into the tumors.
Our general hypothesis is that inhibition of CD93/IGFBP7 to achieve blood vessel normalization will increase T cell infiltration for the treatment of malignant meningiomas. This proposal addresses this unmet need in the treatment of malignant meningiomas as there are limited options currently for patients who have exhausted surgical and radiation options.
Fan Zhang, PhD
Institution: University of Florida
Mentor: Jeffrey Harrison, PhD
Tribute: Fully supported by StacheStrong
A major obstacle for successful immunotherapy for brain tumors is the hostile immune-suppressed tumor microenvironment (TME) that limits treatment efficacy. Tumor-associated macrophages (TAMs) are a diverse population of immune cells derived from various origins such as brain and bone marrow. These cells are the major immune cells that are found in gliomas. The TAMs promote tumor development and influence the effect of the standard-of-care cancer treatments and immunotherapies. Recent studies have indicated that different types of TAMs have different roles in promoting glioma development and influence treatment effect; therefore, these TAM subsets should be targeted separately. Unfortunately, current therapeutics to target TAMs do not differentiate between TAM subsets, and they also have toxicities and limited access to the tumor.
To address this limitation, we propose to develop a novel therapy to selectively target TAM subsets in brain tumors through intravenous infusion. Our previous study has established that this therapy can reach the brain tumor and selectively target TAMs in the tumor. Now, we need to investigate what subset(s) of TAMs are being targeted and whether this therapy would allow reduced side effects. Implemented into the clinic, this therapy will safely modulate TAMs and potentiate standard-of-care treatment or cancer immunotherapies for brain tumor patients. This interdisciplinary study will advance our understanding of how therapeutics interact with specific TAM subsets; and how modulate the TAM subsets can reshape the brain tumor microenvironment for more effective immunotherapy.
2021 Ongoing and Recently Completed Projects
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.
Wajd Al-Holou, MD
Institution: The University of Michigan
Mentor: Maria Castro, PhD
Tribute: In honor of Joel A. Gingras, Jr.
Glioblastoma (GBM) is the most lethal brain tumor with an average survival of around 15 months. This cancer forms from abnormal mutated brain cells that grow out of control and expand through the brain. Despite aggressive treatment, essentially all tumors recur. All previous therapies tested have failed to treat GBM due to the significant differences, or heterogeneity, of the tumor cells. Thus, not only are GBM tumors/cells different between individual patients, but also within an individual tumor each region contains unique cells with unique mutations. To make things even more complicated, research has shown that at the microscopic level, interactions between cancer cells and the normal cells nearby (for example blood vessels, immune and brain cells) protect the cancer cells from treatments. This allows GBMs to easily adapt to therapies and continue growing. We have failed to identify new treatments because we have failed to understand the incredible heterogeneity of GBMs.
Using state-of-the-art genetic technology, we can define cancer cell vulnerabilities by defining their location in relation to nearby cells and their genetic makeup. Our in-depth analysis will allow us to identify ways to target these vulnerabilities to identify new therapies to treat this devastating tumor and follow-up laboratory studies will identify if these therapies have significant impact.
Terrance Burns, MD, PhD
Institution: Mayo Clinic in Rochester, MN
Mentor: Jann N. Sarkaria, MD
Tribute: Supported by Southeastern Brain Tumor Foundation
IDH-mutant gliomas are the most common gliomas of young adults. Despite initial sensitivity to chemotherapy and radiation, they invariably progress into treatment-resistant and ultimately fatal tumors. Translation of novel therapies for glioma is complicated by the lack of biomarkers that indicate treatment effectiveness.
Survival remains the gold standard outcome measure. Clinical trials for patients with IDH-mutant gliomas may require a decade to yield survival results, hampering timely progress in a complex field. When trials fail, as is typically the case, few insights into why the treatment failed are available to guide therapeutic improvements. The cycle is then repeated with new novel candidates leading to a growing list of failed drugs without clear directions for improvement. New tools are urgently needed to accelerate discovery of novel therapies.
Here we propose to evaluate biomarkers from live human IDH-mutant gliomas during surgery, and will compare these to findings from mice carrying human IDH-mutant gliomas. We will also determine if biomarker levels from the live tumor respond to currently available therapies in real time in mice. If so, this work can provide a path forward to more rapidly determine which therapies or combinations are most effective within individual patients. We are optimistic that this strategy can open a new frontier of rapid individualized feedback which is so urgently needed to cure gliomas.
Paul Castillo, MD
Institution: University of Florida
Mentor: Duane Mitchell, MD, PhD
Tribute: Supported by An Anonymous Family Foundation
Lymphomas of the brain are tumors that arise from white blood cells, the infection fighting cells, called B cells, located in the brain. The malignant B cells do not travel to organs outside the central nervous system and thus, they are called primary central nervous system lymphomas. Most of patients who initially present with brain lymphomas get cured but just temporarily. Up to 6 out of 10 patients with this disease will have their lymphoma back months down the road and at this point, this type of cancer is almost never curable with currently available therapies.
Training the immune system via immunotherapy to become soldiers to combat B cell blood cancer (i.e., leukemias and lymphomas) has shown great promise to induce sustainable and high cure rates. However, the current immunotherapies attack B cell cancers that have external markers also shared by normal B cells, thus killing the normal B cells as well. Furthermore, a good number of those patients, even after being “cured” with a given immunotherapy, have their disease back after some time as their tumors learn to escape from their destruction. In this study, we propose a novel strategy to destroy B cell cancer cells while leaving normal B cells by educating the immune system to distinguish between cancer cells and healthy cells. This approach will also target multiple markers as opposed to one or two markers, reducing the chances of escaping to the attack from the immune system and hence, lower chances for the cancer to come back.
Florence Cavalli, PhD
Institution: Curie Institute
Mentor: Olivier Ayrault, PhD
Tribute: Supported by Humor to Fight the Tumor
Cancer cells arise from deregulation of normal cells. Tumors hijack the gene regulation machinery that is responsible for normal development in order to drive tumor development and recurrence. Many studies have focused on identifying tumor-specific genetic events (e.g. mutations) but much less is known regarding the key regulators of gene expression driving the cancer state. I aim to identify and study those key regulators in two major understudied areas: tumor temporal heterogeneity (or differences observed between primary and recurrent tumors), and tumor spatial heterogeneity (or differences observed between the population of cells within a tumor).
These types of heterogeneity are of critical importance since they represent major causes of treatment failure. I will analyze primary-recurrent pair samples of oligodendroglioma tumors, an understudied but a common adult high-grade brain tumor type. Most of these tumors recur and are ultimately fatal. It is therefore critical to further study them. I will study the tumors at a single-cell resolution to identify and compare the key regulators of the cell populations within the tumors. The information from this comparison will reveal the cell of origin of the recurrence from the primary tumors and the common recurrent specific key regulators. I will then propose drug targets to kill the cells that initiate tumor recurrence, to attack them early, before recurrence can begin. This project will provide important novel biological insights which can lead to new therapeutic strategies and to the development of models to study the disease.
Jian Hu, PhD
Institution: University of Texas M.D. Anderson Cancer Center
Tribute: In honor of Joel A. Gingras, Jr.
Glioblastoma (GBM) is the most frequent and deadliest primary brain tumor. With the advent of immunotherapy, a number of cancers previously unresponsive to all types of therapies have been successfully treated and even cured. Unfortunately, immunotherapy in its current form has not been shown to exert a clinical benefit for most GBM patients, probably due to unique composition and features of immune cells found in GBM. Due to certain defects in these immune cells, they have turned themselves from attackers of cancer cells to helpers of cancer cells.
Our previous work has identified a class of important molecular regulators for these immune cells in GBM that could be used for GBM therapy. We have found that two potent and safe drugs that were developed for other diseases could effectively fix the immune cells in GBM and make them able to recognize and attack cancer cells again. Our proposal will help us further understand how these drugs achieve their functions of fixing immune cells and develop better therapeutic approaches by combining with other types of immunotherapies.
Markus Siegelin, MD
Institution: Columbia University
Tribute: Supported by the Sontag Foundation
Glioblastoma (GBM) is the most common primary malignant brain tumor with poor prognosis and essentially no durable treatment. Tumor growth is ultimately determined by nutrients/energy. Tumor tissues have developed unique strategies to enable their growth and to secure their survival under conditions of nutrient absence. Originally considered as a waste product of breaking down sugar for energy and probably better known from exercise physiology, lactic acid accumulates to a significant amount in the infiltrative edge of GBM tumors.
We have made the intriguing observation that in clinically relevant model systems of glioblastoma, lactic acid is heavily utilized for energy in cell culture and more importantly in mouse models. Moreover, lactic acid is critical for glioblastoma cell survival when sugar levels are low. In order to mediate this survival benefit, lactic acid regulates the so called epigenome, which in part is comprised of chemical modifications on the DNA and proteins that ultimately regulate gene expression. Interference with lactic acid mediated regulation of the epigenome using a clinically validated drug, CPI-613 extends animal survival in mice. Following completion of the study our research will establish lactic acid metabolism as a therapeutic target in glioblastoma.
Eric Thompson, MD
Institution: Duke University
Tribute: Supported by An Anonymous Family Foundation
Current adjuvant therapy for the malignant brain tumors medulloblastoma and pediatric high grade glioma (HGG) is marginally effective and often toxic. A promising alternative to current radiochemotherapy is oncolytic viral therapy (OV) which is currently being explored in clinical trials. However, the mechanism of tumor cell death from these OVs are currently unclear. Furthermore, it is unclear why some patients have durable long-term overall survival with OV, while many experience no real benefit.
We have recently discovered that oncolytic viruses cause profound oxidative stress on tumor cells, resulting in cell death. Furthermore, we have found that tumor cells with high levels of anti-oxidants are resistant to OV. Given that one key process by which OV kills cancer cells is the induction of profound oxidative stress, we hypothesize that medulloblastoma and HGG resistance to OV is mediated by the cancer cells’ strong anti-oxidant capacity.
The aim of this project is to determine the specific molecular pathways of oxidative stress of brain tumors that confer resistance to OV. This study will identify genes that change in response to OV in medulloblastoma and pediatric HGG. We hope to identify therapeutics to overcome resistance to OV, resulting in better outcomes for more patients.
Lee Wong, PhD
Institution: Monash University
Tribute: Supported by An Anonymous Family Foundation
Paediatric gliomas are fatal, and are the leading cause of cancer-related mortality in children. The median survival ranges from 12 to 60 months with a 5-year survival of less than 20%. Treatment for paediatric glioma remains an unfulfilled need in clinical neurooncology. Recent DNA sequencing studies have shown that paediatric gliomas often have mutations in histone proteins which help fold and package DNA. Histones are also described as suitcases that sort our DNA to regulate gene activities. In paediatric glioma, histone mutations result in the failures of cells to turn on the right genes and establish the correct identity, therefore, trapping them in a stem cell-like tumour state that divide uncontrollably.
This exciting discovery brings new hope for developing effective therapies for paediatric gliomas. To translate this new knowledge into clinical patient management and patient outcomes, this study will utilise sophisticated DNA and protein technologies to investigate how histone mutations change DNA packaging and trap the cancer in an immortal stem-cell like behavior to drive cancer formation. This study will also identify factors that can restore the normal cell behavior and development to paediatric gliomas. The knowledge gained from this study will identify effective and specific therapeutic targets for paediatric gliomas.
Gelareh Zadeh, MD, PhD, FRCSC, FAANS
Institution: University Health Network
Tribute: Supported by An Anonymous Family Foundation
Currently, diagnosing glioma tumors requires surgery, which is associated with significant anxiety and in some cases may cause complications leading to significant complications and even death. In addition, determining whether a glioma has recurred or is responding to treatment requires imaging, which is not always reliable.
Tumors shed cancer cell DNA into the bloodstream (also called circulating cell-free tumor DNA or cfDNA). Obtaining a sample of cfDNA from blood provides an opportunity to non-invasively ‘biopsy’ tumors to establish a diagnosis for patients’ tumors and avoid unnecessary surgery. We have recently shown in working with our collaborator, Dr. Daniel De Carvalho, that certain changes in cfDNA (so-called DNA methylation) can help diagnose brain tumors. This work was published last year in the journal Nature Medicine.
In this project, we will assess the utility of cfDNA methylation profiling for noninvasive detection of glioma recurrence after treatment and monitoring the tumor’s response to chemotherapy and radiation throughout the course of the treatment. This application of our technology could transform clinical management of glioma patients and reduce the need for high-risk surgical procedures altogether.
