UCSF Brain Tumor SPORE
Specialized Programs of Research Excellence (SPOREs), designated and funded by the National Cancer Institute since 1992, are intended to promote translational research focused on an organ-specific human cancer.
UCSF is one of six institutions to be awarded a SPORE grant for improving the detection, diagnosis, and treatment of brain tumors. We are the only institution to have been continuously funded since brain tumor SPOREs were first established in 2002. Our current SPORE grant is led by Mitchel Berger, MD, with co-leaders Susan Chang, MD, and Hideho Okada MD, PhD, and supports three translational research projects and three resource Cores (Administrative, Biostatistics/Clinical, and Biospecimen/Pathology), all focused on improving the diagnosis and treatment of brain tumors. The opportunity to support early career investigators and foster innovative research projects is facilitated by the Career Enhancement Project and the Developmental Research Project grants managed by Joseph Costello, PhD. The three projects are described in the following sections:
DNA Methylation-Based Blood Biomarkers for Prognosis, Molecular Stratification, and Treatment Response in Glioma Patients
The 2021 WHO classification for gliomas incorporates isocitrate dehydrogenase (IDH) mutations and other molecular features as key diagnostic criteria that distinguish of glioblastoma (GBM) from lower-grade brain tumors. However, survival outcomes and responses to treatment still vary significantly among individual patients. Researchers at UCSF have discovered a powerful genomic profiling method based on the unique DNA methylation fingerprints in the various types of immune cells in the blood. This project aims to help clinicians and patients better understand prognoses, avoid unnecessary interventions, and improve risk stratification for future clinical trials.
- Create survival models for IDH wildtype GBM survival models that integrate longitudinal immune profile data
- Develop a pre-operative blood biomarker to distinguish glioma status by IDH status and grade
- Create predictive blood biomarkers to distinguish pseudoprogression from true early progression in GBM patients after treatment
Novel Hyperpolarized C-13 Imaging as Metabolic Markers of Response in IDH-Mutant Glioma
Hyperpolarized C-13 imaging provides information about dynamic changes in tumor metabolism and has delivered promising results in pre-clinical and patient studies of glioblastoma (GBM). Hyperpolarized C-13 imaging may also help clinicians rapidly determine how well a treatment is working by tracking early changes in metabolism at the tumor site. For example, the isocitrate dehydrogenase (IDH) mutations characteristic of some gliomas result in a decrease in the metabolic conversion of ⍺-ketoglutarate (⍺KG) to glutamate. These tumors instead produce an oncometabolite called 2-hydroxyglutarate.
Led by Pavithra Viswanath, PhD, Yan Li, MD, PhD, and Susan Chang, MD, the objective of this project is use hyperpolarized C-13 imaging to monitor the metabolism of IDH mutant gliomas. The research team will
- Establish the preclinical utility of hyperpolarized C-13 pyruvate and C-13 ⍺KG as metabolic markers of tumor burden and early response to therapy of IDH mutant gliomas
- Assess whether hyperpolarized C-13 pyruvate imaging can be used to define the response of IDH mutant gliomas to therapy
- Test whether data obtained via metabolic imaging improves the assessment of tumor burden in patients with IDH mutant glioma
Novel B-SYNC T Cell Therapy with CNS-specific Expression of CAR as a Safe and Effective Therapy for Glioblastoma
Chimeric antigen receptor T-cell (CAR T) therapies direct the T cells of the immune system to recognize and attack tumor cells. However, in glioblastoma (GBM), these approaches are complicated by the fact that the antigens most often associated with GBM are not present on all the tumor cells or can be found on other cells in the body.
We recently developed a two-stage “prime and kill” strategy that first uses an antigen specific to brain and GBM cells. Then, a synthetic notch receptor (synNotch) directs the T cells to make an antigens that identify and kill only the GBM cells.
- Determine the safety and efficacy of an IV-infusion with B-SYNC T cells in patients with GBM
- Assess potential mechanisms that may mediate resistance to this immunotherapy regimen in preclinical models
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