- Project 1: San Francisco Bay Area Adult Glioma Survival Study
- Project 2: Novel Biomarkers of Malignant Progression in Recurrent Low Grade Glioma (LGG)
- Project 3: Novel Approaches for Improving Pediatric BRAFV600E Glioma Patient Outcomes
- Project 4: Overcoming Local and Peripheral Immune Suppression in Glioma to Facilitate Effective Glioma Therapy
THE SAN FRANCISCO BAY AREA ADULT GLIOMA SURVIVAL STUDY
The goals of this continuing Adult Glioma Survival Study are to identify new germline genetic traits that affect the survival of patients with diverse types of glioma and to integrate these heritable factors with the most recently discovered tumor molecular features that affect survival. To accomplish this we will apply a genome wide association approach to a large population of UCSF, Mayo and TCGA glioma cases and controls. We will confirm and extend our studies using a collaborative network including the Southeastern US glioma study population (GliomaSE).
We will apply a powerful and highly efficient single nucleotide polymorphism (SNP) genotyping platform (Affymetrix 640K Axiom array) to 820 glioblastoma patients and replicate our findings in 693 GBM patients. Only GBM patients treated with standard of care surgery, radiation and temozolomide will be included to minimize variations in treatment on patient outcomes. We will also carry out the first genome wide survival studies in grade II and III infiltrating glioma, using a large population of 1749 cases. Grade II and III patients have substantially longer survival times compared with high grade GBM and offer an even greater chance to uncover new inherited factors important for survival. We will also apply the results of these discovery analyses in grade II and III glioma patients in long standing completed clinical trials to begin to assess the generalizability of our findings to clinical trial populations. Finally, we will use our extensive tumor molecular database for to assess inherited genetic survival factors in glioma molecular subtypes. We have data on the IDH and TP53 mutation status, EGFR amplification and MGMT methylation of tumors that will be combined with inherited genetic information to carry out the first ‘integrative’ genomics’ study of glioma survival.
Building on 10 years of SPORE funding and over 20 years of R01 funding and our extensive and productive ongoing collaborations, this proposal will uncover new patient and tumor prognostic factors for glioma. Understanding their relationship to known factors is crucial not only for greater understanding of glioma pathogenesis and providing accurate assessment to patients about their prognosis, but also potentially for optimal patient stratification for treatment.
NOVEL BIOMARKERS OF MALIGNANT PROGRESSION IN RECURRENT LOW GRADE GLIOMA (LGG)
This study aims to determine whether quantitative parameters derived from magnetic resonance spectroscopy imaging (MRSI) data are predictive of response to therapy for patients with gliomas. This is an important clinical question because gliomas are heterogeneous, infiltrative tumors with poorly defined margins. Although histological grade has been shown to be predictive of outcome in large-scale clinical trials, there is considerable variability between tumors of the same grade in terms of response to therapy and time to progression. The identification of new factors that predict treatment response are critical for tailoring therapy to individual patient characteristics and are expected to have a significant impact upon the criteria used to select patients for future clinical trials.
UCSF laboratory studies have used MRSI to derive a number of different quantitative parameters that are valuable for defining the metabolic activity and spatial extent of tumor. These include a choline to N-acetylaspartate index (CNI), a choline to creatine index (CCrI), a creatine to N-acetylaspartate index (CrNI), and a lactate plus lipid index (LLI). The present study will determine if these indices provide information that is clinically relevant for the management of gliomas and will determine, using patients on clinical trial protocols at UCSF, if there is a basis for integrating the technology into the design of future clinical trials.
NOVEL APPROACHES FOR IMPROVING PEDIATRIC BRAFV600E GLIOMA PATIENT OUTCOMES
Backgound and hypothesis. Currently we are faced with a lack of effective, FDA approved interventions to control glioma in children. BRAFV600E mutations occur at significant frequencies in several histopathologic subtypes of pediatric glioma. Small molecule inhibitors specific for BRAFV600E have been developed that show remarkable efficacy in treating BRAFV600E melanoma, and we have recently shown that a BRAFV600E inhibitor significantly extends the survival of animal subjects with intracranial BRAFV600E glioma xenografts. We feel that incidence of BRAFV600E in pediatric patients with glioma combined with the availability of an effective therapeutic against BRAFV600E tumors constitute a compelling basis for testing BRAFV600E therapy in treating children with BRAFV600E brain tumors.
Although we are excited about our results, we have identified feedback mechanisms that help BRAFV600E tumor cells compensate for and ultimately escape BRAF inhibition. However, we have also identified approaches for disrupting compensatory feedback signaling, and that can be used to improve upon the results of BRAF inhibitor monotherapy. Specifically, the use of secondary inhibitors, that target distinct enzymatic activities, and that are administered concurrently with a BRAF inhibitor result in increased anti-proliferative effect and survival extension of animal subjects with intracranial BRAFV600E glioma. These results indicate the need for developing combination therapy approaches for maximizing anti-tumor effect and achieving durable disease relief for pediatric patients with BRAFV600E glioma. This is the objective of our research, as conducted in association with the following specific aims:
- Aim 1. Investigate Mechanisms That Limit BRAF Inhibitor Sensitivity in BRAFV600E Gliomas.
- Aim 2. Investigate 2-agent combinations for relative efficacy, both with and without concurrent radiation therapy (RT), and analyze tumor specimens for adaptation to sustained treatment.
- Aim 3. Evaluate BRAF targeted therapy in patients with BRAFV600E pediatric glioma.
Given the unmet need for improved treatment of this cancer in this patient population, combined with the unique opportunity to target a newly discovered, biologically relevant mutation, and the expertise of our research team in translating laboratory-based findings into clinical action, we will test BRAF inhibitor therapy for pediatric BRAFV600E glioma, and anticipate this research to have significant, positive benefit for children with this currently incurable cancer.
OVERCOMING LOCAL AND PERIPHERAL IMMUNE SUPPRESSION IN GLIOMA TO FACILITATE EFFECTIVE GLIOMA THERAPY
The long-term translational goal of this project is to overcome mechanisms of immunoresistance that diminish efficacy of immunotherapy for glioma patients, particularly glioblastoma (GBM). In the previous cycle we completed a Phase I clinical trial and a Phase II clinical trial for recurrent GBM patients immunized with an experimental vaccine, after surgical resection. These trials demonstrated that autologous glioma-derived heat shock protein peptide complex-96 (HSPPC-96) vaccine is safe, evokes a CD4+ and CD8+ tumor specific T-cell response and increases survival of recurrent GBM patients as compared to historical controls. In the previous SPORE cycle we also identified proteins that contribute to glioma immunoresistance, including B7-Homologue 1 (B7-H1) that is expressed on the glioma cell surface, induces CD8+ T-cell apoptosis and is positively regulated by PI(3)K. Our observations explain how the PI(3)K/B7-H1 pathway can directly inhibit T-cell killing of tumor. In the next cycle of this project we plan to test the hypothesis that immunosuppressive tumor effects of PI(3)K/B7-H1 pathway activation can also be mediated indirectly, through expansion of the regulatory T cell (Treg) pool (Aim 1) and through expression of B7-H1 protein on tumor infiltrating macrophages (Aim 2) in patients with low grade astrocytoma (LGA), anaplastic astrocytoma (AA), and GBM. To determine the clinical impact of PI(3)K/B7-H1 pathway activation on response to glioma immunotherapy we will initiate a randomized trial comparing the standard of care (intravenous bevacizumab) to HSPPC-96 combined with bevacizumab in recurrent GBM patients (Aim 3).