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Last Updated: 10/17/18

BRAIN TUMOR SPORE

University of California, San Francisco

INVESTIGATOR CONTACT INFORMATION

Mitchel S. Berger, MD
University of California, San Francisco
Department of Neurological Surgery
505 Parnassus Avenue, Room M-786
San Francisco, California 94143
Tel: (415) 353-3933
Fax: (415) 353-3910
Email: bergerm@neurosurg.ucsf.edu

PROJECT 1: BLOOD IMMUNOMETHYLOMIC MARKERS OF OUTCOME IN GLIOBLASTOMA PATIENTS

Project Co-Leaders:
John Wiencke, Ph.D.
Annette Molinaro, PhD
Jennifer Clarke, MD

Glioblastomas (GBM) are devastating central nervous system tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and peripheral blood compartments. The development of novel markers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of myeloid derived suppressor cells. This gap in our understanding is a recognized high priority in the new era of cancer immunotherapy. The Cancer Moonshot blue ribbon panel recommended as a key actionable goal “to develop approaches to overcome an obstructive, immune-suppressive tumor environment in both children and adults”. Our project addresses this important goal by developing and testing a powerful method for immune profiling that is based on unique immune cell DNA methylation fingerprints. Using this novel immunomethylomic approach for immune profiling in Aim 1 we will serially assess immune status in a large group of patients with newly diagnosed GBM from their initial diagnosis through their surgery, radiation and chemotherapy treatments. To identify clinical correlates of treatment response and tumor recurrence at each point we will also assess each patient’s MRI scans. In Aim 2 we will then assess the prognostic value of methylation generated immune profiles (myeloid derived suppressor cells, CD4, CD8, T-cells, B-cells, NK, monocytes, and neutrophils) and other factors in GBM patient survival and progression. In Aim 3 we will evaluate how the new information on patient immune profiles can influence clinical decision making. The end result of these studies will enable clinicians and patients to better understand their prognosis, avoid unnecessary interventions, and improve risk stratification for future clinical trials.

PROJECT 2: MONITORING METABOLISM IN GBM USING HYPERPOLARIZED C-13 IMAGING AND H-1 MRSI

Project Co-Leaders:
Sarah Nelson, PhD
Susan Chang, MD

The objective of this project is to combine hyperpolarized C-13 imaging and H-1 MR spectroscopic imaging (MRSI) data in order to detect differences in dynamic and steady state metabolism that can be used to improve the evaluation of patients with glioblastoma (GBM). Conventional anatomic imaging provides ambiguous results that make it difficult to decide if patients have responded to therapy or progressed. While current H-1 MRSI methods give robust measures of the spatial extent of abnormal metabolism through values of the choline to N-acetylaspartate index (CNI), additional parameters are required to better distinguish recurrent tumor from treatment related effects and to detect rapid changes following treatment. Hyperpolarized C-13 pyruvate imaging is a new MR imaging method that provides information about dynamic changes in metabolism and has provided promising results in pre-clinical and patient studies of GBM. Understanding how hyperpolarized C13 pyruvate imaging can be combined with more established steady state H-1 MRSI and conventional anatomic imaging is critical for improving patient care. Specific Aim 1 will apply these two metabolic imaging strategies to patients with newly diagnosed GBM at the pre-RT and the first post-RT follow-up scan. Rates of conversion of pyruvate to lactate and bicarbonate will be evaluated in normal appearing brain, the anatomic lesion and the CNI lesion in order to determine whether they improve the definition of residual tumor. Specific Aim 2 will use metabolic imaging to target locations for tissue sampling in patients undergoing surgery for suspected recurrence. The goal will be to validate H-1 and C-13 parameters as markers of recurrent tumor vs treatment related effects. Specific Aim 3 will obtain metabolic imaging from patients suspected to have recurrent GBM and being treated with standard of care therapies, and will test the hypothesis that lactate/pyruvate ratio will be an earlier indicator of response than choline to N-acetylaspartate index (CNI). This will be critical for determining whether these metabolic markers can be used as early indicators of response to therapy.

PROJECT 3: A NEW THERAPEUTIC TARGET FOR TERT PROMOTER MUTANT GLIOMA

Project Co-Leaders:
Joeseph Costelo, PhD
Mitchel S. Berger, MD

The goal of this project is to develop GABP as a therapeutic target to reverse immortality of tumors harboring a mutant telomerase reverse transcriptase (TERT) promoter. TERT promoter mutation affects over 80% of GBM and oligodengroglioma (OD). Due to a lack of TERT transcription in somatic cells, telomeres shorten with each successive cell division until they reach a critical level that triggers senescence and limits cell lifespan. Reactivation of TERT expression overcomes these barriers, enabling tumor cells to proliferate indefinitely. Although proteins controlling mutant TERT promoter reactivation and tumor cell immortalization may be ideal therapeutic targets, the exact identity of these molecules remained unknown. We discovered that a single ubiquitously expressed transcription factor, GABP, uniquely bound to the mutant TERT promoter and drove TERT reactivation in TERT-promoter-mutant glioma and other cancers. In our preliminary data, we identify a specific heterotetramer forming GABPΒ1 isoform (GABPΒ1L) that is dispensable in normal cells but may be critical for mutant TERT promoter activation and tumor cell immortalization. If the mutant TERT promoter is uniformly present throughout each tumor, and if GABPΒ1L modulation leads to tumor cell death while sparing normal cells, the GABP pathway may represent a new therapeutic option for mutant TERT promoter-driven malignancies. We will test this hypothesis with three specific aims: In Aim 1, we will determine the extent to which the TERT promoter mutation is clonal at diagnosis and recurrence. In Aim 2, we will use CRISPR-Cas9 genetic targeting of the GABPB1L isoform to determine if the GABP heterotetramer is required to maintain cellular immortality in TERT promoter mutant CNS tumors. In Aim 3, we will perform a focused, exploratory screen of DNA-damaging and DNA damage response-inhibiting agents on GABPΒ1L deficient cells to identify therapies that will increase cell death and decrease tumor formation. These studies could establish the GABPΒ1L isoform as a valuable therapeutic target for TERT promoter mutant CNS tumors, and potentially many others.

PROJECT 4: TARGETING 4EBP1 ON GLIOBLASTOMA

Project Co-Leaders:
William Weiss, MD, PhD
Nicolas Butowski, MD

Although signaling from phosphoinositide 3-kinase (PI3K) to the mechanistic target of rapamycin (mTOR) features prominently in glioblastoma, inhibitors that target PI3K and mTOR have failed in patients with glioblastoma. In published and preliminary data presented in this application, we identified the mTOR target p4EBP1 as a robust biomarker for therapeutic response. We further show that the failure of PI3K and mTOR inhibitors tested in glioblastoma patients is not because these targets and pathways are unimportant, but because agents used clinically fail to target 4EBP1. We have now identified and tested a new class of 4EBP1 inhibitors that potently block 4EBP1 in glioblastoma in-vivo, leading to robust improvement in survival in preclinical orthotopic models of GBM. Our proposal develops this class of drugs for clinical use, evaluating a clinical 4EBP1 inhibitor, and providing a precision medicine path forward for a clinical trial in patients with glioblastoma. This clinical agent, Rev1, is available collaboratively with Revolution Medicines, and this SPORE incentivizes testing of Rev1 in glioma. We will test Rev1 in an early phase clinical trial by year 4 for this SPORE. The SPORE mechanism therefore provides a unique opportunity to test the hypothesis that clinical agents derivatized from RapaLink-1 represent potent clinical inhibitors of 4EBP1, and will be highly active in relevant subpopulations of GBM. Our specific aims are: Aim 1. To define the optimal glioma sub-population for clinical trials using inhibitors of 4EBP1 Aim 2. To optimize the efficacy of 4EBP1 inhibitors for clinical development. Aim 3. To design and conduct a phase IB clinical trial with Rev1 in pathway-activated recurrent glioblastoma.

CORE 1: BIOSPECIMEN / PATHOLOGY CORE

Core Co-Directors:
Joanna J. Phillips, M.D., Ph.D.
Arie Perry, M.D.

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, multi-modality preservation, integrated histopathologic and molecular annotation, and a computerized inventory, request and tracking system. In order to maximize sharing and integration of SPORE projects, the Biospecimen Core collects and makes available data derived from all distributed brain tumor biospecimens. The Specific Aims are:

  1. To procure brain tumor patient biospecimens from the operating room and from animal 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 Projects and clinical trials.
  2. To perform quality control assays on archived biospecimens collected from the operating room and animal models, to ensure availability of adequate numbers of consistently handled specimens that will yield high-quality data for SPORE projects and clinical trials.
  3. To provide standardized routine and advanced tissue handling/processing and analytical techniques, including immunohistochemistry, fluorescence in situ hybridization, tissue microarray construction, DNA/RNA extraction, protein isolation, and preparation of viable cells that will allow each Project to fulfill its goals.
  4. To maintain a SPORE Biospecimen/Pathology Core database containing demographic data, integrated histopathologic and molecular annotation, results from molecular analyses, and tissue distributions (internal and external) that will be linked to relational clinical databases maintained by the SPORE Biostatistics and Clinical Core and used by all Projects.

CORE 2: BIOSTATISTICS / CLINICAL CORE

Core Co-Leaders:
Annette Molinaro, PhD
Susan Chang, MD

The Biostatistical and Clinical Core will provide the expertise needed to support the laboratory and clinical research of all four SPORE Projects and the Developmental Research and Career Enhancement projects. The Biostatistical Co-leader is Annette Molinaro, PhD, who will provide advice on the design of experimental and clinical studies, including the clinical trial in Aim 3 of Project 4; data analysis guidance (either by performing the analyses within the core or advising qualified personnel within the projects), including the use of appropriate statistical models and applications of statistical test; and, when appropriate, the development of novel methods to help interpret results from experiments. Under Dr. Molinaro’s supervision, the Core has established and will expand and maintain the UCSF Brain Tumor Center Database, which will be the primary, centralized repository for annotated data used by all SPORE investigators. This unique and customizable resource will connect clinical information to imaging, tissue, and genomic parameters generated by the SPORE projects. The Clinical Co-leader, Susan Chang, MD, will interact with all Project leaders in the planning and conduct of the clinical studies and assessment of results. This includes reviewing the prognostic value of the blood immunomethylomics results from the population science studies in Project 1; assess the effect of novel metabolic imaging studies planned in patients in Project 2 as they relate to important clinical endpoints; and to interpret the results of Projects 3 and 4 to determine whether they can be used to reliably stratify patients by specific biological pathways in future clinical trials. The Core will oversee all clinical studies, provide clinical research nurses and data coordinators, and assist in all of the required regulatory and compliance reporting.

ADMINISTRATIVE CORE

Core Co-Leaders:
Mitchel S. Berger, MD
Susan Chang, MD
Joseph Costello, PhD

The UCSF Brain Tumor SPORE has three overall specific objectives: to identify factors that contribute to the likelihood of surviving brain cancer, to identify noninvasive imaging parameters that can help predict therapeutic response in patients with glioma, and to develop better mechanism-based therapies for the treatment of brain cancer. The Administrative Core 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 specific aims of the Core are: 1) To evaluate research progress. The Administrative Core, through the SPORE Executive Committee, the SPORE Steering Committee, and the SPORE EAB, will be responsible for evaluating the progress of projects and making decisions regarding the continuation or replacement of projects. 2) To provide fiscal management. The Administrative Core distributes all funds, and provides timely reporting of finances to Project Leaders and the SPORE PI/co-PIs. 3) To provide administrative support. The Administrative Core will be responsible for the daily operations of the SPORE, for the preparation of SPORE-related manuscripts, and for communications with NIH. 4) To facilitate communication between SPORE investigators and between the SPORE and outside entities. The Administrative Core schedules all meetings, seminar series, and retreats, and distributes the notices inviting participation in the Career Enhancement Program and the Developmental Research Program. 5) To assist in compliance. The Administrative Core will be responsible for assuring compliance and scientific integrity of all components of the SPORE. The Administrative Core will be used by all Projects, Programs, and Cores in the SPORE.