The Lower Grade Glioma Research Collective

As survival time for patients with low-grade glioma is generally longer than for patients with high-grade glioma, much of the funding for glioma has focused on high-grade tumors, resulting in a slower pace of research for low-grade tumors. The loglio consortium was formed by philanthropists Ashley and Alan Dabbiere in order to connect brain tumor researchers all over the country to tackle the problem of low-grade glioma in collaborative groups. 

Loglio provides funding for novel, high-risk research that may not be eligible for traditional funding mechanisms. Successful preliminary results from loglio studies have been leveraged into nearly $39 million of additional funding for low-grade glioma research from the NIH and other funding sources. 

Scroll down to learn about the specific areas of research currently supported by loglio. To support low-grade glioma research at UCSF, visit makeagift.ucsf.edu. 

Accomplishments:

• 15 NIH grants and trainee fellowships resulting from loglio discoveries 
• 4 Industry collaborations to pursue targeted therapies for lower grade gliomas
• 2 Clinical trials of immunotherapies against lower grade gliomas
• Over 50 publications (including Science, Nature, New England Journal of Medicine)
• 19 Presentations at the 2019 Annual Scientific Meeting of the Society for Neuro-Oncology

 

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Risk and Classification

This project studies the immune profiles of low-grade gliomas to determine if they can be correlated with better or worse outcome. Researchers at UCSF, Mayo Clinic, Yale and USC are using a relatively new type of immune profiling called immunomethylomics, which is a DNA-based method that quantifies immune cells based on the DNA methylation signatures of different immune cell subsets. The researchers hope that immune profiles may be integrated with other known prognostic markers to more accurately predict a patient's clinical course.

Aims:

• Aim 1: Create immune profiles for patients with lower grade glioma
• Aim 2: Develop risk loci and risk models for specific lower grade glioma subtypes

 

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Metabolic Imaging of Response to Mutant IDH Inhibitors

IDH mutation is a genetic signature of oligodendroglioma. This project aims to develop biomarkers of IDH mutation that can be quantified with 13C hyperpolarized imaging techniques, giving clinicians information about recurrence or response to treatment faster than standard anatomic imaging.  

Aims:

• Aim 1: Identify 1H and hyperpolarized 13C MRS-detectable changes in mutant IDH1 cell models
• Aim 2: Assess the translational value of biomarkers identified in cells by investigating in vivo animal models
• Validate the metabolic biomarkers by determining the mechanistic underpinnings of the metabolic alterations

 

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A Therapeutic Target for TERT-promoter-mutant Tumors

TERT promoter mutations are present in more than 80 percent of glioblastoma multiformes and oligodendrogliomas and are thought to play an important role in tumor cell immortality. Work by UCSF Brain Tumor Center PI Joseph Costello, PhD, and his colleagues recently identified GABP as the molecule responsible for binding to the mutant TERT promoter and activating it (thus lengthening the telomeres of tumor cells and allowing them to avoid natural cell death). This area of research is delving into the feasibility of creating therapies to inhibit GABP and preventing aberrant TERT expression.

Aims:

• Aim 1: Determine if inhibiting GABPb1L and GABPb2 in actively growing tumors will increase survival of mice bearing TERTp mutant glioblastoma or oligodendroglioma
• Aim 2: Determine the structure of the GABP tetramer bound to the mutant TERTp

 

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Immunotherapy Approaches for Low-Grade Glioma

Immunotherapy has become an increasingly promising field for cancer therapy, including brain tumor therapy. In this project, immunology specialist Hideho Okada, MD, PhD, is examining whether several existing immunotherapies developed for high-grade gliomas could also be useful for treating low-grade gliomas, as well as developing new therapies that target antigens commonly found on LGG cells.

Aims

• Aim 1: Determine whether glioblastoma lysate-based vaccines will induce T-cell responses in low-grade glioma.
• Aim 2: Determine whether the anti-CD27 monoclonal antibody varlilumab enhances efficacy of IMA950 vaccines in low-grade tumors
• Am 3: Development of T-cell receptor (TCR)-based therapy targeting carefully selected LGG-associated antigens

 

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Immunogenomics of Low-Grade Glioma

One complication in treating glioma is that the tumor cells develop different mutations over time, especially during progression from low-grade glioma to high-grade glioma. Yet another complication is that a mutation found in one tissue sample may not be representative of the entire tumor. With a 3-D immunogenomics approach, investigators of this project will collect and analyze samples across the tumor volume. Using this approach at initial diagnosis and at recurrence, researchers can identify neoantigens that are present throughout the tumor and persist over time. These antigens may be better targets than those found using single-sample analysis.

Aims:

• Establish spatial and temporal neoantigen landscapes using 3D-biopsy and paired oligodendroglioma cases.
• Functionally validate neoantigens and determine whether the presence of high-quality neoantigens in the site is associated with immunological characteristics of the oligodendroglioma microenvironment. 

 

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Low-Grade Glioma Genome (LG3) Project

Aims

• Aim 1: Develop patient-derived cell line model of a triple-positive human oligodendroglioma and an IDH mutant astrocytoma that are hypermutated
• Aim 2: Determine the clinical significance of hypermutation in IDH1 mutant lower grade glioma
• Aim 3: Determine if MGMT promoter methylation in initial tumors predicts which tumors will hypermutate after treatment with temozolomide.

 

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Noninvasive Characterization of Oligodendroglioma (NICO)

NICO investigates imaging markers of related to molecular features of oligodendroglioma. By improving imaging protocols, we hope to better evaluate response to treatment and recurrence.

NICO Project 1: Multimodal Imaging Features Associated with Tumor Progression

Goal: Improve specificity of imaging methods for patients with lower grade glioma (LrGG) by combining anatomic imaging, diffusion imaging, contrast perfusion imaging, and metabolic imaging parameters.

NICO Project 2: Improving sensitivity and specificity for imaging the IDH1 mutation

Goal: Develop the first-ever sterile hyperpolarized agent pharmaceutical preparations for C2-pyruvate & a-ketoglutarate and launch first human studies for imaging the IDH mutation.

NICO Project 3: Imaging the functional consequences of TERT promoter mutation

Identify the 1H MRS-detectable changes associated with TERT expression in cell models and test hyperpolarized 13C probes for monitoring TERT expression with the goal of translating potential biomarkers to animal models.

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Loglio Cognitive

The impact of treatment interventions for lower grade gliomas on cognition and health-related quality of life (HRQOL) are not well understood. Surgery, radiation therapy, and chemotherapy can all affect information processing, memory, attention, executive functioning, and behavior. This project aims to develop rehabilitation strategies that can help mitigate effects of treatment and help patients with daily functioning at critical time points during treatment, as well as after treatment has stopped and the disease is stable.

Interventional Aims:

• Aim 1: Evaluate feasibility of cognitive rehabilitation strategies in stable lower grade glioma
• Collect preliminary data on interventions
• Correlate with tumor characteristics and imaging

Longitudinal Aims:

• Prospectively follow newly diagnosed lower grade glioma patients
• Identify timing of clinically meaningful cognitive change
• Correlate with tumor characteristics and imaging parameters

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Pilot Projects

Circulating Serum Exosomes as Prognostic Markers of Lower Grade Glioma (PI: Stephen Francis, PhD)

Low-grade Glioma Models Core (PIs: Bjoern Schwer, PhD, and William Weiss, MD, PhD)