2023 GRANT Award Details

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.

SEED GRANT

Grantee: City of Hope
Project Lead: Darya Alizadeh, PHD
Grant Title: Advancing IL13Ra2-CAR T cell Therapy against Glioblastoma by Enhancing IFN-Signaling
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2023
Amount: $50,000
Duration: 1 year

Summary: Glioblastoma (GBM) - the most common and aggressive form of brain cancer- is among the deadliest cancers affecting adults and children. The average length of survival for GBM patients is estimated to be only 8 months. Despite aggressive standard-of-care therapies, tumor recurrence is almost inevitable and uniformly lethal. Survival rates and mortality statistics for GBM have been virtually unchanged for decades.

Given the current dearth of effective therapeutic options for these patients and the modest effects of various immunotherapies evaluated to date, it is of critical urgency to identify novel strategies for future clinical evaluation. Cancer immunotherapy has revolutionized treatment options for many solid tumors, including brain cancers. Chimeric Antigen Receptor (CAR) T cells, a form of cellular immunotherapy, are a type of immune cells engineered with a synthetic receptor to recognize cancer cells. CAR T cell therapy has shown tremendous impact in hematological cancers but have faced some challenges in solid tumors. One of the challenges in CAR T cell therapy of solid tumors, such as GBM, is the suppressive tumor environment, which prevents both CAR T cells and patient’s immune cells from recognizing the tumor. However, one immune cell type (myeloid cells), is found abundantly in brain tumors. We have previously shown that the immune stimulating factor (IFNγ) secreted by activated CAR T cells has the ability to potently change myeloid cell function to become anti-tumor immune cells.

This proposal aims to improve CAR T cell therapy for brain tumors by engineering our CAR T cells to enhance IFNγ signaling, which will not only promote CAR T anti-tumor function but increase their ability to reprogram resident myeloid cells against the tumor. Our preliminary studies have shown that this approach is promising and feasible. This approach will condition glioma tumors to be more susceptible not only to CAR T therapy, but other treatment options that could increase the overall survival of patients. Lastly, the success of this proposal will also generate a technology platform for the treatment of other challenging cancers that lack effective treatment options.

SEED 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
Amount: $50,000
Duration: 1 year

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.

SEED GRANT

Grantee: MD Anderson Cancer Center
Project Lead: Sachet Shukla, PHD
Grant Title: Identification of non-canonical antigens of development of novel immunotherapies in Glioblastoma
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2023
Amount: $50,000
Duration: 1 year

Summary: Immunotherapies belong to a category of treatments that activate a patient's own immune system to target their cancer cells. However, their effectiveness is limited to only a small subgroup of glioblastoma (GBM) patients. T cells play a crucial role in launching an effective immune response against tumors by recognizing "antigens," which are small protein fragments produced due to DNA or RNA changes within cancer cells. Therefore, it is essential to accurately and comprehensively identify these DNA and RNAalterations in GBM to discover new antigens suitable for developing safe and efficient immunotherapies. Typically, commercially available molecular tests focus on short-read sequencing methods and identify salterations in protein-coding regions of the genome, known as "canonical" antigens. However, these regions make up only a tiny fraction (0.3%) of the entire genome. Other alterations in cancer cells, such as structural DNA changes or the expression of abnormal RNA molecules, can impact the entire genome, giving rise to a substantial number of relevant "non-canonical" antigens. Advanced third-generation long-read sequencing technologies, in combination with other molecular profiling and computational methods, have the potential to be highly effective in discovering these new non-canonical antigens. Surprisingly, these approaches have not been applied to GBM research so far, representing an untapped opportunity to identify new immunological targets for therapy. Therefore, our primary goal in this study is to employstate-of-the-art long-read sequencing on GBM samples to comprehensively identify non-canonical antigens. This effort will drive the development of innovative immunotherapies for 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 and 2023
Amount: $100,000
Duration: 2 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, and 2023
Amount: $250,000
Duration: 5 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 and 2023
Amount: $100,000
Duration: 2 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.

F.L.A.G. GRANT

Grantee: Children’s Hospital Los Angeles
Project Lead: Dr. Katrina O’Halloran & Dr. Ashley Margol
Grant Title: Cerebrospinal fluid liquid biopsy in pediatric embryonal central nervous system tumors
Grant Type: F.L.A.G Grant
Year Awarded: 2023
Amount: $50,000
Duration: 1 year

Summary: Brain and spinal cord tumors continue to be a major cause of both illness and death in children. Tumor DNA sequencing has provided important insight into the drivers of different cancers. Detecting tumor DNA in spinal fluid by performing DNA sequencing as a “liquid biopsy” can help in making a diagnosis, monitoring response to treatment, and predicting risk for relapse. For example, researchers have shown that if medulloblastoma DNA is detectable at the completion of therapy, there is higher risk for relapse for that child.

Liquid biopsy technology using spinal fluid has been developed at Children’s Hospital Los Angeles. In pilot studies, the platform successfully detected a variety of tumor DNA alterations in various tumors including medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor, diffuse midline glioma (including diffuse intrinsic pontine glioma), high grade glioma and low-grade tumors (including pilocytic astrocytoma). In this project we propose serial spinal fluid liquid biopsy assessments in children diagnosed with embryonal brain and spinal cord tumors.  Liquid biopsies will be performed at diagnosis, during treatment, at the end of therapy, during surveillance and at relapse.

Importantly, results of liquid biopsy testing will be provided as a report and the clinical team may use this information to modify and optimize treatment.  In numerous prior patients, a liquid biopsy in conjunction with the overall clinical picture has led to a change in therapy for personalized treatment. It is our hope that this technology will help to improve outcomes for children with brain and spinal cord tumors.