This project will use novel quantitative imaging methods to guide biopsies to biologically distinct regions of primary and post-treatment recurrent GBM for targeted exome, epigenome and transcriptome analysis. Our goal is to identify naturally evolving and treatment-induced mutations and epimutations that promote the selective outgrowth of malignant subclones over lime. Genomic analysis of cancer is typically conducted at a single time point and on a single piece of the bulk resection without knowledge of its original context within the heterogeneous tumor. In contrast to these traditional genomic studies, an image guided approach to newly diagnosed and recurrent tumors could enrich for the detection of drivers of tumor growth by linking mutations and epimutations to regions of aggressive tumor growth in vivo. We will use innovative metabolic and physiologic imaging to identify regions with different levels of proliferation and hypoxia within the same patient. To our knowledge, this would be the first time that advanced imaging will be used to guide genomic or epigenomic analysis of any human tumor.
In Aim 1, we will identify functional mutations and epimutations that exhibit intratumoral heterogeneity within newly diagnosed GBM.
In Aim 2, we will identify functional mutations and epimutations commonly acquired during tumor progression using image guided tissue samples from treated, recurrent GBM, including paired samples from individual patients over time. Our preliminary data show that chemotherapy can have a profound effect on selective outgrowth of malignant subclones. The integration of data from Aims 1 and 2 will identify subclones in newly diagnosed tumor that exhibit selective outgrowth to become the dominant clone(s) at recurrence, and the sequential biallelic events involving intersecting genetic and epigenetic mechanisms that contribute to their enhanced growth potential. Candidate driver alterations will be evaluated using a mature computational pipeline, and will experimentally be tested for predicted functional effect. These studies could therefore impact patient care by the identification of common drivers specific to recurrence, defining the influence of therapy on tumor evolution, and incorporating profiles of primary and recurrent tumors into personalized treatment plans.

Public Health Relevance

State-of-the-art genomics and epignomics techniques will be guided by advanced imaging and tissue analyses to comprehensively characterize regional heterogeneity and evolution of glioblastoma. We hope to identify driver mutations and mutations that are uniquely associated with tumor progression, including therapy induced mutations. This will better inform the design of clinical trials and assist clinicians in tailoring treatment in individual patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-2)
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University of California San Francisco
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Lupo, Janine M; Molinaro, Annette M; Essock-Burns, Emma et al. (2016) The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma. Neuro Oncol 18:87-95
Mazor, Tali; Pankov, Aleksandr; Song, Jun S et al. (2016) Intratumoral Heterogeneity of the Epigenome. Cancer Cell 29:440-51
Park, Ilwoo; von Morze, Cornelius; Lupo, Janine M et al. (2016) Investigating tumor perfusion by hyperpolarized (13) C MRI with comparison to conventional gadolinium contrast-enhanced MRI and pathology in orthotopic human GBM xenografts. Magn Reson Med :
Johannessen, Tor-Christian Aase; Mukherjee, Joydeep; Viswanath, Pavithra et al. (2016) Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis. Mol Cancer Res 14:976-983
Cao, Peng; Shin, Peter J; Park, Ilwoo et al. (2016) Accelerated high-bandwidth MR spectroscopic imaging using compressed sensing. Magn Reson Med 76:369-79
Larson, Peder E Z; Han, Misung; Krug, Roland et al. (2016) Ultrashort echo time and zero echo time MRI at 7T. MAGMA 29:359-70
Radoul, Marina; Chaumeil, Myriam M; Eriksson, Pia et al. (2016) MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival. Mol Cancer Ther 15:1113-22
Bell, Robert J A; Rube, H Tomas; Xavier-Magalhães, Ana et al. (2016) Understanding TERT Promoter Mutations: A Common Path to Immortality. Mol Cancer Res 14:315-23
Nelson, Sarah J; Li, Yan; Lupo, Janine M et al. (2016) Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab. J Neurooncol 130:171-179
Cao, Peng; Zhang, Xiaoliang; Park, Ilwoo et al. (2015) (1) H-(13) C independently tuned radiofrequency surface coil applied for in vivo hyperpolarized MRI. Magn Reson Med :

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