2024-25 GRANT Award Details
SEED GRANT
Grantee: University of California, San Francisco
Project Lead: John Liu, MD, PHD
Grant Title: Defining neural dependent vulnerabilities in GBM radiation sensitization using functional genomics
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2024
Amount: $50,000
Duration: 1 year
Summary: Glioblastoma (GBM) is the most common malignant brain tumor and is highly fatal. Radiotherapy (RT) is the backbone for treating GBM, but these tumors almost always recur even where the radiation dose is highest. It has been appreciated that interactions between neurons and GBM cells promote the growth of GBM tumors. We have recently developed genome-wide CRISPR/Cas9 functional genomics tools to discover new genetic targets and radiation sensitizers in models of brain tumors. However, it is not known how neuron-tumor interactions affects RT resistance in GBM, and genome-wide efforts to discover neuraldependent RT sensitizers have not been performed. The objective of this proposal is to understand how neuron-tumor interactions affect RT resistance genome-wide in both tumor cells and neurons, in order to identify gene targets that could maximize the benefits while minimizing the side effects of RT for patients living with GBM.
SEED GRANT
Grantee: City of Hope
Project Lead: Qi Cui, PHD
Grant Title: Targeting non-coding RNA pseudouridine modification for glioblastoma therapy
Grant Type: UKF Seed Grant
Year Awarded: 2024
Amount: $50,000
Duration: 1 year
Summary: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is believed that GBM stem cells (GSCs) confer the treatment resistance and tumor recurrence for GBM. In this study, we aim to define the role of pseudouridine modification of non-coding RNA in GBM with the aim to develop novel GBM therapies by targeting this pathway. Specifically, we will investigate the regulation of noncoding RNA pseudouridine modification on GSC growth and tumorigenesis and the underlying mechanisms in this study. If successful, this study will lay a foundation for novel therapeutic development for GBM by targeting RNA pseudouridine modification and its regulatory pathways.
SEED GRANT
Grantee: Duke University
Project Lead: Yiping He, PHD
Grant Title: Sirpiglenastat for treating glioblastoma
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2024
Amount: $50,000
Duration: 1 year
Summary: Glioblastoma is a highly aggressive and deadly brain cancer because the tumor cells quickly become resistant to treatments like chemotherapy, radiation, and immunotherapy. This resistance happens because the tumor cells adapt to therapies that aim to kill them, and they also create an environment that weakens the immune system's response. A key group of molecules called purines, which serve as building blocks and energy sources for cells, plays a major role in these processes. Normally, tumor cells get purines by both recycling them and making them from scratch. However, about 50% of glioblastoma cases involve a genetic mutation that stops the tumor cells from recycling purines, making them entirely dependent on producing purines from scratch. This means that blocking this purine production could be an effective way to treat these cases. Our prior research showed that blocking purine production can work in glioblastoma animal models, but the drug used was too toxic for clinical use. Recently, we have discovered that a new, lower-toxicity prodrug - originally intended to treat prostate cancer in our research - can effectively inhibit purine production from scratch. We confirmed that this strategy not only directly attacks the prostate cancer cells but also boosts the immune system's ability to fight the cancer, leading to better results with fewer side effects in animal models. Subsequent preliminary studies suggest that this prodrug could also be effective in treating glioblastoma by killing tumor cells and reducing their ability to suppress the immune system. This project aims to further test the prodrug in different glioblastoma models to determine its effectiveness, with the hope of developing a new treatment strategy that could improve outcomes when combined with existing therapies in about half of glioblastoma cases.
SEED GRANT
Grantee: The University of Alabama at Birmingham
Project Lead: Satoru Osuka, MD, PHD
Grant Title: Targeting Recurrent Glioblastoma Cells Using Collagen-Binding IL-12 and IL-7
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2024
Amount: $50,000
Duration: 1 year
Summary: This project aims to develop a new treatment for recurrent glioblastoma. We have created special forms of two immune-boosting proteins, CBD-IL-12 and CBD-IL-7, that can target the unique environment of glioblastoma tumors. These modified proteins are designed to accumulate in the tumor area without affecting healthy tissues, potentially reducing side effects. By combining these two proteins, we hopes to stimulate the immune system to fight tumor cells more effectively, particularly by preventing immune cells from becoming "exhausted" in their battle against the tumor. The study will test this approach in mouse models of recurrent glioblastoma to determine if it can shrink tumors and extend survival. If successful, this research could lead to a new, safer, and more effective treatment option for patients with recurrent glioblastoma, addressing a critical need in brain cancer therapy.
RENEWAL GRANT
The Kristen Grossman SEED GRANT
Grantee: Duke University
Project Lead: Peter Fecci, MD, PHD
Grant Title: The CARE-BEAR Proposal
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2023 and 2024 renewal
Amount: $100,000
Duration: 2 years
Summary: Immunotherapies have been notoriously unsuccessful against glioblastoma (GBM) to date. A critical problem facing these approaches is the substantial antigenic heterogeneity that GBMs exhibit. Such heterogeneity has been particularly limiting for CAR T cells, which classically target protein antigens on the surface of tumor cells. Needed are novel means for targeting GBM in a manner that bypasses the typical limitations imposed by tumor heterogeneity.
Our group has recently discovered that the decades-old model for how T cells target and kill tumor cells is incomplete. The traditional model requires that T cells recognize their target antigens solely in the context of MHC molecules and, thus, that GBM and other tumors can escape immune detection by downregulating MHC on their surface. We have found that T cells remain quite capable of killing tumor cells lacking MHC and do so in a manner that bypasses the classical need for T cells to encounter their target antigens on tumors entirely. Instead, T cells prove capable of recognizing a ligand that is both highly and homogenously expressed by tumor cells (particularly those tumor cells lacking MHC), called NKG2DL (Lerner E. et al, Nature Cancer 2023).
This newly discovered mechanism provides an opportunity for bypassing the traditional immunotherapeutic dependence on heterogeneous protein antigens and instead proffers a homogenous tumor target in NKG2DL. We have therefore begun constructing a novel therapeutic that targets both protein antigen and NKG2DL. This proposal is aimed at initial optimization and testing of this platform, en route to ultimate clinical translation.
This grant was made in memory of our dear friend, Kristen Grossman.
RENEWAL GRANT
Grantee: Weill Cornell Medicine
Project Lead: Claire VanPouille-Box, PHD
Grant Title: Regulation of myeloid cells by fatty acid metabolism in irradiated Glioblastoma
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2023 and 2024
Amount: $100,000
Duration:2 years
Summary: Glioblastoma (GBM) is a brain cancer that affects adults and children and cannot currently be cured. Over 15 years, more and more patients will be diagnosed with GBM while no advances in care have been achieved. Thus, more people will die from GBM in the future. Radiation therapy (RT), in which the tumor is hit with a targeted beam of radiation to kill cancer cells, is one of the standards of care for GBM and is often the only option for brain tumors that cannot be surgically removed. In multiple cancers, RT acts as a vaccine that starts an immune response against cancer. When activated against cancer cells, the body’s immune system is a very powerful anti-cancer therapy. However, GBMs inevitably return, suggesting that RT fails to sustain anti-tumor immunity. Understanding why RT is incapable of stimulating the immune system against GBM is critical to developing long-lasting brain cancer treatments that will exploit the patient’s own immune system to kill cancer cells. It is well-known that brain cancers do not have a lot of immune cells to fight against GBM, which makes it difficult for immunotherapy to work. Our preliminary data show that RT of brain cancers increases the production of lipids via the fatty acid synthase (FASN) to prevent immune activation and support tumor progression.
So, we think that stopping FASN will prevent the production of lipids in irradiated GBM, and this in turn will deny GBM cells the protection against the immune system. As a result, we predict that blocking FASN will augment tumor cell kill and stimulate the immune system against the tumor. Overall, this project aims to validate FASN targeting as a novel treatment strategy to unleash anti-tumor immunity in irradiated GBM.
RENEWAL GRANT
Grantee: University of California Los Angeles
Project Lead: Aparna Bhaduri, PHD
Grant Title: Characterizing PTPRZ1 Mechanism in Cancer as a Therapeutic Target
Grant Type: UKF Seed Grant
Year Awarded: 2022, 2023 and 2024
Amount: $150,000
Duration: 3 years
Summary: Glioblastoma (GBM) is the most common and most aggressive form of adult brain cancer. Unfortunately, most patients succumb to the disease within 12 – 18 months of diagnosis as limited treatment options exist. In our previous work, we identified that a cell type that exists in the developing human brain is reactivated as a cancer stem cell. This population, called “outer radial glia” are highly marked by a gene called PTPRZ1 which sits on the cell surface. Importantly, this outer radial glia are very common in human brains during development but very rare in mice, making them hard to study in mouse or rat models of brain development and GBM. This gene, PTPRZ1, has also been shown by others to be required for GBM progression and spread across the brain. These pieces of data indicate that PTPRZ1 should be a tantalizing drug target, especially because it sits partly on the outside of tumor cells. However, the existing literature on PTRPZ1 is conflicted regarding whether its catalytic activity (its functional pocket) is or is not required for tumor progression. This study seeks to characterize how PTRPZ1 works in GBM, to then design a drug to interfere with its function and limit its ability to promote GBM progression.
RENEWAL GRANT
Grantee: MD Anderson Cancer Center
Project Lead: Vidya Gopalakrishnan, PHD
Grant Title: Repurposing Migraine Treatments for DIPG
Grant Type: UKF Seed Grant and 3 renewals
Year Awarded: 2019, 2020, 2021, 2022, 2023 and 2024
Amount: $300,000
Duration: 6 years
Summary: Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. It represents nearly 10% of all pediatric central nervous system tumors. Approximately 80% of human DIPGs exhibit a recurrent H3K27M mutation and 75% of these are found in the H3F3A gene, which encodes histone H3.3. The less than two-year survival rate in patients highlights the desperate need for treatments.
With the support of the Uncle Kory Foundation, Dr. Gopalakrishnan and her team at The University of Texas MD Anderson Cancer Center in Houston, Texas, have discovered that a protein called REST is expressed at higher levels in DIPG tumors than in normal tissue and is required for DIPG growth. A REST-context specific chemical screen using re-purposable drugs identified candidates that target cell-surface receptors controlling cell-cell communication in the nervous system as having potential for therapeutic evaluation. Pre-clinical studies with cell culture and mouse orthotopic models of DIPG confirmed that DIPG cells harboring the H3K27M mutation were indeed more sensitive to these drugs than DIPG tumors expressing wildtype histones and that REST elevation further increased their drug sensitivity. Future studies will be two-pronged. The first will be directed at clinical translation of the above findings through Phase I/II studies. The fact that these agents are already used in children to treat neurological disorders will facilitate our application to the FDA requesting their study in patients with DIPG. The second will involve multi-omics studies to understand the molecular characteristics of tumor cells that respond and those that don’t. This will allow us to develop combination treatments to target the non-responders.
The Gopalakrishnan group are very grateful to the Uncle Kory Foundation and their team for their support in getting a high-risk project off the ground!
F.L.A.G. RENEWAL GRANT
Grantee: University of Southern California
Project Lead: Josh Neman, PHD
Grant Title: The role of GABA transaminase in medulloblastoma local recurrence and its potential as a therapeutic target in medulloblastoma metastasis
Program Area: Medulloblastoma - Pediatrics
Grant Type: F.L.A.G Grant
Year Awarded: 2022, 2023 and 2024
Amount: $150,000
Duration: 3 years
Summary: Medulloblastoma is a pediatric brain tumor that has a propensity to locally recur and to spread to other regions of the brain and spinal cord. Patients with these diagnoses will almost always succumb to their disease, highlighting the importance of performing research on these phenomena. When medulloblastoma tumors recur, cancer cells that were left over from tumor resection surgery evolve, adapt, and become resistant to chemotherapy and radiation treatments. They begin to grow more aggressively than the original tumor, are difficult to treat, and have limited treatment options. Likewise, when medulloblastoma spreads to the spine, called metastasis, treatment is extremely difficult as surgery and radiation/chemotherapy have immense risks. The current proposal uses our strong foundational understanding of medulloblastoma, brain development, and neuroscience to 1) advance our understanding of medulloblastoma local recurrence and 2) develop targeted therapies for patients with medulloblastoma metastases that are safe. We hypothesize that medulloblastoma will exploit a protein called GABA Transaminase, also known as ABAT, to survive in the harsh conditions caused by radiation and chemotherapy and allow medulloblastoma to recur. Moreover, because metastatic medulloblastoma are dependent on ABAT to grow, as our recent publication has shown, we hypothesize that a new potential ABAT inhibitor, NEO216, will serve as a safe and effective targeted therapy for patients. These studies will have potential near-term impact on understanding how the pediatric brain tumor medulloblastoma recurs and how we can directly target medulloblastoma metastases – the principal reasons for patient mortality. Overall, the findings from our proposed research plan will reduce the burden on patients and their families, will improve their quality of life, and most importantly, increase the overall survival of pediatric patients who suffer from this terrible disease.