F.L.A.G Awardees

Grantee: The University of Texas MD Anderson Cancer Center
Project Lead: Max Wintermark, MD, MS, MBA
Grant Title: Autophagy inhibition to sensitize medulloblastoma to enhance NK cell immunotherapy
Grant Type: F.L.A.G Grant
Year Awarded: 2025
Amount: $50,000
Duration: 1 year

Summary: Medulloblastoma (MB) is the most common malignant brain tumor in children. While treatments like surgery, radiation, and chemotherapy are standard, they often lead to severe long-term side effects, especially in developing brains. Despite advances in classifying MB into molecular subtypes—Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4—therapeutic progress has been slow, particularly for the SHH and Group 3/4 subtypes, which tend to have poor outcomes.

This research explores the potential of natural killer (NK) cell immunotherapy as a novel treatment option for MB. NK cells are part of the immune system that can attack cancer cells without the need for specific antigens, making them promising for pediatric cancers, which typically have fewer mutations. However, MB tumors create a hostile environment for NK cells, partly due to autophagy, a process that helps tumor cells survive under stress and develop resistance to NK cell therapy. The study aims to improve NK cell therapy by blocking autophagy pharmacologically, which may sensitize MB tumors to immunotherapy. 

This work is innovative in several ways: it seeks to make MB tumors more susceptible to immune-based treatments, and introduces a new imaging method for monitoring NK cells in the brain, If successful, this strategy could offer a new, less toxic option for treating recurrent or hard-to-treat MBs, improving outcomes for children who have limited options with existing treatments.

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: 2024
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.

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.