Glioblastoma (GBM; WHO grade IV) is the most frequent primary brain tumor and has a dismal prognosis. A common goal in neuro-oncology is to develop therapies targeted at molecular mechanisms of tumor progression. One potential detractor to such approaches is the tremendous heterogeneity within a given patient's GBM, such that molecular targets could vary depending on the micro-environment from which they are sampled. Following neurosurgical resection of these highly infiltrative tumors, it will be criticalto direct therapies at druggable targets present at the residual invasive tumor near the resection margin, rather than at those of the bulk resected tumor, since these could differ substantially. Our preliminary data and the literature suggest that transcriptional programs and EGFR/PDGFRA amplification events vary across regions within GBM. Downstream signaling networks and druggable targets likely show similar variation. We initiated a Phase II clinical tria of 5-Aminolevulinic Acid (5-ALA), a fluorescent compound that accumulates in glioma cells, thereby enhancing visualization and neurosurgical resection and allowing definition of macro-environments that include 1) perinecrotic glioma, 2) bulk glioma, and 3) glioma margin. Using this novel neurosurgical platform, we propose to define spatial and temporal molecular variations of human GBMs including transcriptional and phospho-protein profiles, EGFR/PDGFRA amplification and downstream network activation by multiplex quantum dots. We also investigate molecular alterations that evolve within recurrent GBM in patient samples as compared to those present at the tumor margin of the primary tumor. A GBM xenograft model in which hypoxia and necrosis are induced using photo-activated compounds that cause vaso-occlusion will be used to precisely monitor spatial and temporal evolution of molecular variation. We hypothesize that the transcriptional profiles, genomic amplification, and druggable tyrosine kinases vary spatially and temporally, and will differ at the residual tumor margin as compared to the bulk tumor.

Public Health Relevance

Glioblastoma (GBM) is a highly malignant brain tumor that is generally fatal within 18 months. The therapeutic targeting of specific molecular alterations that drive tumor biology remains a goal in neuro-oncology. It will be critical to determine spatial variations in druggable targets, including those at the residual invasive margins in order to treat most effectively. Utilizing a novel platform for visualizing the distinct tumor environments at the time of neurosurgery, the current proposal attempts to define molecular targets within specific regions with a special focus on the invasive margin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA176659-04
Application #
9063107
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Lively, Tracy (LUGO)
Project Start
2013-06-06
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Brat, Daniel J; Aldape, Kenneth; Colman, Howard et al. (2018) cIMPACT-NOW update 3: recommended diagnostic criteria for ""Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV"". Acta Neuropathol 136:805-810
Lakomkin, Nikita; Hadjipanayis, Constantinos G (2018) Non-routine discharge disposition is associated with post-discharge complications and 30-day readmissions following craniotomy for brain tumor resection. J Neurooncol 136:595-604
Halani, Sameer H; Yousefi, Safoora; Vega, Jose Velazquez et al. (2018) Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways. NPJ Precis Oncol 2:24
Mukherjee, Subhas; Tucker-Burden, Carol; Kaissi, Emily et al. (2018) CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells. Cell Rep 23:1651-1664
Zhang, Pengyue; Wang, Fusheng; Teodoro, George et al. (2017) AUTOMATED LEVEL SET SEGMENTATION OF HISTOPATHOLOGIC CELLS WITH SPARSE SHAPE PRIOR SUPPORT AND DYNAMIC OCCLUSION CONSTRAINT. Proc IEEE Int Symp Biomed Imaging 2017:718-722
Rossetti, Blair J; Wang, Fusheng; Zhang, Pengyue et al. (2017) DYNAMIC REGISTRATION FOR GIGAPIXEL SERIAL WHOLE SLIDE IMAGES. Proc IEEE Int Symp Biomed Imaging 2017:424-428
Zhang, Changming; Mukherjee, Subhas; Tucker-Burden, Carol et al. (2017) TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3. Mol Oncol 11:280-294
Zhang, S; Qi, Q; Chan, C B et al. (2016) Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity. Cell Death Differ 23:52-63
Selagea, Ligia; Mishra, Alok; Anand, Monika et al. (2016) EGFR and C/EBP-? oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-? isoform. FASEB J 30:4098-4108
Hinrichs, Benjamin H; Newman, Scott; Appin, Christina L et al. (2016) Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups. Acta Neuropathol Commun 4:4

Showing the most recent 10 out of 19 publications