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Last Updated: 09/21/23

Brain Tumor SPORE Grant

University of California, San Francisco

Principal Investigator(s):

Mitchel Burger, MD
Mitchel Burger, MD

Principal Investigator(s) Contact Information

Mitchel Burger, MD
Director, Brain Tumor Center
Professor, Department of Neurological Surgery
University of California, San Francisco
505 Parnassus Ave
San Francisco, California 94143
(415)-353-3933

Overview

Despite recent advances in the understanding of the biology of gliomas, treatments for these brain tumors remain limited. This SPORE proposal has three overall goals: 1) to identify factors that contribute to the likelihood of surviving brain cancer; 2) to identify noninvasive imaging parameters that can help predict therapeutic response in patients with glioma; and 3) to develop better mechanism-based therapies for the treatment of brain cancer. At the heart of the proposal are three translational research projects — each intended to evaluate paradigm-changing novel tools for prognostic, diagnostic, and therapeutic modalities with defined human endpoints.

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Project 1: DNA Methylation-Based Blood Biomarkers for Prognosis, Molecular Stratification, and Treatment Response in Glioma Patients

Project Co-Leaders:
Annette Molinaro, PhD (Basic Co-Leader)
John K. Wiencke, PhD (Basic Co-Leader)
Jennie W. Taylor, MD, MPH (Clinical/Applied Co-Leader)

IDH mutation and other genetic features of glioma have changed the landscape of diagnosis and prognosis for lower-grade glioma; however, these markers do not explain the heterogeneity in treatment response and survival in patients with glioblastoma (GBM). To determine whether individual immune factors play a role in glioma outcomes, Project 1 investigators pioneered immunomethylomics — an approach to define and quantitate a comprehensive library of immune cell populations (e.g., naïve and memory CD4 and CD8 T-cells, B cells, NK cells, monocytes, and neutrophils) and aberrant MDSCs from fresh or frozen peripheral whole blood. Immunomethylomics is a robust method based on DNA methylation patterns in immune cell genomes.

Specific Aims:

Aim 1: Create integrated IDH wildtype GBM survival models with longitudinal immune profile data.

Aim 2: Create a pre-operative blood biomarker for enhancing and nonenhancing lesions to distinguish high-grade IDH mutant gliomas from IDH-wildtype GBM.

Aim 3: Create predictive blood biomarkers to distinguish pseudo progression from true early progression in GBM patients after chemotherapy and radiation.

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Project 2: Novel Hyperpolarized 13C Imaging as Metabolic Markers of Response in IDH-Mutant Glioma

Project Co-Leaders:
Pavithra Viswanath PhD (Basic Co-Leader)
Yan Li MD, PhD (Translational/Applied Co-Leader)
Susan Chang, MD (Clinical Co-Leader)

In the 2021 WHO classification, the first criterion for diagnosis of adult glioma is IDH mutation. This functional mutation results in the conversion of αKG to a novel oncometabolite 2HG, thereby decreasing the conversion of αKG to glutamate. With new targeted therapeutic strategies being evaluated for IDH mutant glioma, noninvasive, easily acquired measures of the pharmacodynamic effect of these agents are needed. The objective of this project is to assess the early response to therapy and characterize tumor burden by using novel hyperpolarized 13C MRI approaches (hyperpolarized [2-13C] pyruvate or [1-13C] α-KG to monitor the metabolism of IDH mutant glioma.

Specific Aims:

Aim 1: Establish the preclinical utility of hyperpolarized [2-13C] pyruvate and [1-13C] α-KG as metabolic markers of tumor burden and early response to therapy of IDH mutant gliomas.

Aim 2: Determine whether hyperpolarized [2-13C] pyruvate metabolic imaging can define the response of IDH mutant gliomas to therapy.

Aim 3: Determine whether hyperpolarized [1-13C] α-KG imaging improves the characterization of tumor burden in IDH mutant glioma.

This project has the potential to identify spectroscopic, noninvasively derived imaging parameters and linked biomarkers that will help predict tumor recurrence and outcome in patients with IDH mutant glioma.

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Project 3: Novel B-SYNC T Cell Therapy with CNS-specific Expression of CAR as a Safe and Effective Therapy for Glioblastoma

Project Co-Leaders:
Hideho Okada, MD, PhD (Basic Co-Leader)
Jennifer Clarke, MD, MPH (Clinical/Applied Co-Leader)

Current chimeric antigen receptor (CAR)-T cell therapies for GBM have three major limitations. First, most of them — including the FDA-approved anti-CD19 CAR against B-cell malignancies — target a single antigen. However, solid tumors have marked antigenic heterogeneity, so a tumor that does not express the target antigen will recur (antigen-loss escape). Second, constitutive expression of CAR on T cells often leads to exhaustion of CAR T cells due to antigen- independent but continuous activation signals from the CAR (tonic effects). Third, and perhaps most importantly, CAR T cells can recognize the expression of the target on normal cells, causing “on-target off-tumor” toxicities that can be fatal. To target GBM-associated antigens safely and effectively, investigators in Project 3 adopted a novel synthetic Notch (synNotch) receptor system and developed innovative T-cell circuits that recognize tumor cells based on the “prime-and-kill” strategy. In this system, the first antigen, brevican, is expressed exclusively on cells in the central nervous system and induces a CAR against Epha2 and IL-13Rα2 on GBM cells. This project will test the safety and efficacy of this B-SYNC T-cells in patients with GBM in a phase I clinical trial. The investigators will also assess potential immunoregulatory resistance mechanisms.

Specific Aims:

Aim 1: Determine the safety as well as the homing and priming status (i.e., expression of CAR) of the IV-infused B-SYNC T cells in patients with GBM.

Aim 2: Assess potential resistance mechanisms and integrate mitigation strategies into the B-SYNC regimen in preclinical syngeneic models.

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Administrative Core

Core Co-Directors
Mitchel Berger, MD
Susan Chang, MD
Hideho Okada MD PhD

The Administrative Core of the UCSF Brain Tumor SPORE supervises the activities of the UCSF Brain Tumor SPORE and provides fiscal management, administrative support, and the framework by which researchers can communicate and interact. The Administrative Core, through the SPORE Executive Committee, the SPORE Steering Committee, and the SPORE EAB, evaluates the progress of projects and makes decisions regarding the continuation or replacement of projects. The Administrative Core also distributes funds from the SPORE Award, the Career Enhancement and Developmental Research Programs, SPORE Supplement Awards, and discretionary funds provided by the institution. The Administrative Core carries out the daily operations of the SPORE and prepares SPORE-related manuscripts. Additionally, the Core facilitates communication between SPORE investigators and between the SPORE and the NIH, NIH-funded entities, and the brain tumor patient community. This includes scheduling meeting, seminar series, and retreats as well as soliciting participation in the Career Enhancement Program and the Developmental Research Program. Finally, the Administrative Core assures compliance and scientific integrity of all components of the SPORE. The Administrative Core is used by all Projects, Programs, and Cores in the SPORE.

Specific Aims:

Aim 1: To evaluate research progress.

Aim 2: To provide fiscal management.

Aim 3: To provide administrative support.

Aim 4: To facilitate communication between SPORE investigators and between the SPORE and outside entities.

Aim 5: To assist in compliance.

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Biospecimen/Pathology Core

Core Director:
Joanna Phillips, PhD

The UCSF Brain Tumor SPORE Biospecimen/Pathology Core provides staff and technology dedicated to the procurement, processing, storing, distribution, and histopathologic analysis of high-quality brain tumor biospecimens for translational science research. Our mission is to enhance biospecimen quality and utility through use of optimized standard operating procedures, multimodality preservation, integrated histopathologic and molecular annotation, and a computerized inventory, requesting and tracking system. These biospecimens are essential to the success of all SPORE projects and brain tumor translational research at UCSF. In addition, we have expanded the procurement and analysis of image-guided biopsies to include acquisition of multiple, spatially mapped samples from diffuse glioma. We also continue to develop and utilize novel assays to assess human brain tumors for the SPORE projects including gene sequencing, mRNA analysis, in situ hybridization, and immunoassays for mutant proteins and altered signaling pathway activities.

Specific Aims:

Aim 1: To acquire and preserve high-quality brain tumor patient biospecimens from the operating room and from preclinical models used by the Projects with optimized handling to maximize cell viability and/or minimize the cold-ischemia time, so as to meet the tissue accrual requirements for all of the proposed Brain Tumor SPORE projects and clinical trials.

Aim 2: To provide standardized routine and advanced tissue handling/processing and analytical techniques, including multiplex immunofluorescence, multiplexed protein and RNA assays, tissue microarray construction, quantitative whole slide image analysis, DNA/RNA extraction, and preparation of viable cells that will allow each SPORE project to fulfill its goals.

Aim 3: To provide biospecimen and neuropathology expertise to ensure optimal biospecimen quality and extraction of high-quality data from biospecimens collected from the operating room and animal models. This includes performing quality control assays on archived biospecimens and extraction of appropriate quantitative and semi-quantitative parameters from whole slide images.

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Biostatistics/Clinical Core

Core Co-Directors
Annette Molinaro, PhD (Biostatistics Co-Leader)
John de Groot, MD (Clinical Co-Leader)

The Biostatistics/Clinical Core assists in the design of and accrual to clinical studies, in establishing procedures for data storage and transfer, in setting up the study tracking procedures, and in conducting statistical analyses. Specifically, the Clinical Component of the core prepares clinical research protocol documents, establishes protocol and data management tools prior to study initiation, ensures the regulatory compliance in clinical protocols, and assists project leaders in preparing materials for presentation and publication. Additionally, the Clinical Component supports physicians and nurses in administering and monitoring responses to investigational agents used in the clinical studies. The Biostatistics Component finalizes the design of studies, establishes data quality assurance procedures, and manages the existing imaging and tissue database as well as the clinical trials database. The Biostatistics Component also assists the clinical staff in setting up tracking procedures for the clinical studies.

Specific Aims:

Aim 1: To provide expertise on the design, initiation, and conduct of clinical research studies. This will include statistical input on the primary and secondary planned analyses, supplementary studies for validation, and exploratory analyses.

Aim 2: To provide personnel and infrastructure support for all aspects of data management.

Aim 3: To provide regulatory oversight and management of clinical protocols.

Aim 4: To provide research support for the conduct of clinical studies and ensure compliance with protocol requirements.

Aim 5: To assist Project leaders in preparing materials for presentation and publication.

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Developmental Research Program

Program Director
Joseph Costello, PhD

The Developmental Research Program (DRP) is an integral part of the UCSF Brain Tumor SPORE and represents the best opportunity to explore new ideas as pilot projects, to develop new resources, to apply new technologies to translational brain tumor research, and to promote collaborations among scientists at UCSF and outside institutions. In this manner the DRP ultimately serves as a means to build and support new technologies, to support the early-stage development of projects that can compete successfully for peer reviewed funding, and, in the best-case scenario, for inclusion as full projects in the SPORE Program.

Specific Aims:

Aim 1: Support research projects that can generate a strong publication record

Aim 2: Support high-risk/high-impact projects

Aim 3: Help develop collaborations among scientists within UCSF and at different institutions

Aim 4: Develop new ideas as pilot projects to replace SPORE projects or generate outside funding.

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Career Enhancement Program

Program Director
Joseph Costello, PhD

The Career Enhancement Program (CEP) exists to identify, support, and mentor candidates with promising independent careers in translational brain tumor research. The CEP also represents an opportunity to encourage new and established non-translational investigators, including women and under-represented minorities (URM), to consider careers in translational brain tumor research. In this manner the program ultimately serves to expand translational brain tumor research, as well as a source of translational projects and investigators for the UCSF Brain Tumor SPORE Program itself.

Specific Aims:

Aim 1: To identify, support, and mentor individuals with promising careers in translational brain tumor research.

Aim 2: To encourage new and established investigators to develop careers in translational brain tumor research.

Aim 3: To encourage women and URM candidates to pursue careers in translational brain tumor research.

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Institutional SPORE Website

https://braintumorcenter.ucsf.edu/research/ucsf-brain-tumor-spore

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