Glioblastoma is the most common and lethal of brain tumors claiming the lives of over 12,000 people each year in the U.S. alone. Median survival following diagnosis is approximately 15 months with maximal surgical resection, radiation, and temozolomide chemotherapy (standard of care). The challenges inherent in developing better and more effective treatments for glioblastoma are becoming increasingly clear. Glioblastomas are relentlessly invasive, resistance to standard treatments, genetically complex and molecularly adaptable, and contain subpopulations of cancer cells with phenotypic similarities to normal neural stem cells which are often referred to as glioma stem-like cells (GSC).
The microenvironment around cells is extremely rich in information. This includes localized signals from adjacent cells (cell-cell contact) and the surrounding extracellular matrix, as well as soluble molecules produced and secreted by distant cells and organs. Collectively, these signals constitute the tissue context, and the behavior of every cell is profoundly influenced by the precise combination of signals presented to it. Non neoplastic cells respond to these signals in ways that serve the body. In contrast, cancer cells react to their tissue context quite differently and in most cases they actively remodel the microenvironment to promote tumor progression and invasion.
My laboratory is primarily focused on the identification and targeting of cancer-cell intrinsic signaling nodes which are activated by signals from the tumor microenvironment.
1) Cellular adaptation to hypoxia and nutrient deprivation orchestrated by hypoxia inducible factors (HIFs) and the MonoCarboxylate Transporter-4 (MCT4). We have recently reported that hypoxia increases the percentage of GSCs in GBM cultures and in primary tumors and implicated HIFs and MCT4 in this response. Hypoxia has also been shown to promote radiation resistance and tumor invasion, suggesting that an improved understanding of how reduced oxygenation and nutrient availability modulate the pathobiology of glioblastoma will be necessary if we are to effectively treat these universally fatal neoplasms. We are actively engaged in preclinical testing of pharmacological agents that target these pathways in glioblastoma.
2) Crosstalk between microenvironmental factors and “stemness” signaling pathways. We have previously implicated Hedgehog, Notch, and other developmentally significant signaling pathways in the initiation and progression of Medulloblastoma and Glioblastoma. Increasing evidence suggest these pathways may be regulated not only by intrinsic but also by microenvironmental factors. Targeting microenvironmental factors which contribute to the induction of these pathways may lead to novel therapeutic approaches against glioblastomas and other tumors.
3) Mechanisms of drug resistance. Using array CGH technology, we showed that alterations activating the oncogene BRAF are common in pediatric low grade gliomas (>60% of Pilocytic Astrocytomas). We are currently investigating mechanisms of drug resistance in this complex group of tumors.
- Lim KS, Lim KJ, Price AC, Orr BA, Eberhart CG, Bar EE: Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner, Oncogene 2013
- Bar EE: Glioblastoma, cancer stem cells and hypoxia, Brain Pathol 2011, 21:119-129
- Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG: Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres, Am J Pathol 2010, 177:1491-1502
- Bar EE, Stearns D: New developments in medulloblastoma treatment: the potential of a cyclopamine-lovastatin combination, Expert Opin Investig Drugs 2008, 17:185-195
- Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma, J Neuropathol Exp Neurol 2008, 67:878-887
- Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG: Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma, Stem Cells 2007, 25:2524-2533
- Bar EE, Chaudhry A, Farah MH, Eberhart CG: Hedgehog signaling promotes medulloblastoma survival via Bc/II, Am J Pathol 2007, 170:347-355