This revised SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the UCSF Helen Diller Family Comprehensive Cancer Center to apply their expertise to translational research focused on brain cancer. The proposal has four overall specific objectives: 1) to identify factors that contribute to the likelihood of surviving brain cancer;2) o identify imaging parameters and linked tissue biomarkers that predict recurrence and outcome in patients with low grade glioma;3) to develop improved therapies for pediatric brain tumors harboring BRAF mutations;and 4) to improve immunotherapy for brain cancer. At the heart of the proposal are four translational research projects. Project 1 will identify genetic variations associated with survival in low-grade glioma and GBM patients, and will integrate survival genes identified in genome-wide association studies with IDH mutation and other molecular characteristics in the best example of integrative genomics pertaining to glioma survival to date. Project 2 will assess the ability of the spectroscopic markers identified in the previous funding period to predict time to progression and overall survival in low-grade glioma patients. The project also includes a first-ever analysis of the mutations that drive low-grade glioma formation and progression and which may help link genetic alterations to the spectroscopic changes noted. Project 3 is new to this proposal and will build on seminal studies that identified BRAF mutations in pediatric brain tumors. The project will preclinically evaluate new combinations of mechanism-based BRAF, MEK, and cyclin-dependent kinase inhibitors as well as initiate the first clinical trials of BRAF inhibitors in the pediatric brain tumor population. Project 4 will determine the impact of the PI(3)K//B7-H1 pathway on expansion of immunomodulatory T-cells and macrophages, and will investigate the utility of inhibiting PI(3)K/B7-H1 to augment immunotherapy in a clinical trial for GBM patients. This SPORE proposal also requests support for the Career Development and Developmental Research Programs, and four Cores (Administrative, Biospecimen/Pathology, Animal, and Biostatistics and Clinical) that will support the efforts of the four projects.
Despite the best efforts of neurosurgeons and neuro-oncologists, both the incidence and mortality rates of brain cancer have remained stable over the past 20 years, and in 2010 alone, over 12,000 individuals died from brain cancer. The work described in this SPORE application is intended to increase our understanding of this disease, as well as to apply what we learn in the clinical setting, and in the process to improve the lives of individuals with brain cancer.
|Disney-Hogg, Linden; Sud, Amit; Law, Philip J et al. (2018) Influence of obesity-related risk factors in the aetiology of glioma. Br J Cancer 118:1020-1027|
|Goode, Benjamin; Mondal, Gourish; Hyun, Michael et al. (2018) A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 9:810|
|Takahashi, Hannah; Cornish, Alex J; Sud, Amit et al. (2018) Mendelian randomisation study of the relationship between vitamin D and risk of glioma. Sci Rep 8:2339|
|Amirian, E Susan; Ostrom, Quinn T; Armstrong, Georgina N et al. (2018) Aspirin, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-Analysis. Cancer Epidemiol Biomarkers Prev :|
|Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7|
|Disney-Hogg, Linden; Cornish, Alex J; Sud, Amit et al. (2018) Impact of atopy on risk of glioma: a Mendelian randomisation study. BMC Med 16:42|
|Wang, Qianghu; Hu, Baoli; Hu, Xin et al. (2018) Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell 33:152|
|Salas, Lucas A; Wiencke, John K; Koestler, Devin C et al. (2018) Tracing human stem cell lineage during development using DNA methylation. Genome Res 28:1285-1295|
|Ostrom, Quinn T; Kinnersley, Ben; Wrensch, Margaret R et al. (2018) Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21. Sci Rep 8:7352|
|Salas, Lucas A; Koestler, Devin C; Butler, Rondi A et al. (2018) An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biol 19:64|
Showing the most recent 10 out of 362 publications