Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways (1). Despite current therapies, the prognosis for GBM is poor and mean survival remains less than 2 years. An improved understanding of the mechanisms driving abnormal cell signaling is essential for improving treatment outcomes. The long-term goal of this innovative proposal is to define tumor-microenvironment interactions critical in brain cancer and identify clinically relevant, druggable therapeutic targets. Specifically, we focus on the role of extracellular heparan sulfate proteoglycans (HSPGs) as they regulate the activity of multiple ligand-mediated signaling pathways (2), are altered in malignant brain tumors (3, 4), and have the potential to influence both tumor cells and critical tumor-microenvironment interactions, including the tumor-associated microglia/macrophage response. HSPGs, present on the cell surface and in the extracellular matrix, regulate signaling via their ability to bind and alter the bioavailability of diverse ligands, including growth factors, morphogens, chemokines, and enzymes. SULF2, an extracellular heparan sulfate endosulfatase, actively regulates HSPG-dependent signaling by removing the sulfate from 6-O- of glucosamine (6OS) and liberating protein ligands from HSPG sequestration (5). Alterations in HSPG core protein expression and SULF2 expression are common in diverse cancers and the PI of this proposal has shown SULF2 can drive carcinogenesis in malignant astrocytoma through regulation of RTK signaling pathways. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their HSPG substrates are present in the extracellular environment and have great potential as novel therapeutic targets.
Our Aims are:
Aim 1 : In human infiltrating astrocytomas, identify the alterations in HSPG expression and sulfation associated with tumor malignancy.
Aim 2 : Determine HSPG changes driving tumor biologic behavior, including microglia/macrophage response to tumor.
Aim 3 : Identify how HSPG alterations activate signaling pathways to promote GBM malignant behaviors. The proposed research will determine the mechanisms by which alterations in HSPGs drive oncogenic cell signaling pathways in malignant brain cancer and validate HSPGs as clinically relevant, novel therapeutic targets. Successful completion of these studies provides a preclinical basis to study agents that target HSPGs as a novel therapeutic option in malignant brain cancer.

Public Health Relevance

The mortality rates for primary malignant brain cancer have remained stable despite substantial advances in our understanding of disease biology. In the present proposal we will use innovative approaches to define how alterations in the tumor microenvironment drive oncogenic signaling pathways critical in brain cancer and identify clinically relevant, druggable therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS081117-02
Application #
8551786
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2012-09-30
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$331,770
Indirect Cost
$120,676
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wood, Matthew D; Reis, Gerald F; Reuss, David E et al. (2016) Protein Analysis of Glioblastoma Primary and Posttreatment Pairs Suggests a Mesenchymal Shift at Recurrence. J Neuropathol Exp Neurol 75:925-935
Phillips, Joanna J; Gong, Henry; Chen, Katharine et al. (2016) Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation. Acta Neuropathol 132:757-760
Lindberg, Olle R; McKinney, Andrew; Engler, Jane R et al. (2016) GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity. Oncotarget :
Butowski, Nicholas; Colman, Howard; De Groot, John F et al. (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol 18:557-64
Mack, Stephen C; Agnihotri, Sameer; Bertrand, Kelsey C et al. (2015) Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype. Clin Cancer Res 21:3750-8
Singer, Mark S; Phillips, Joanna J; Lemjabbar-Alaoui, Hassan et al. (2015) SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis. Clin Chim Acta 440:72-8
Mazor, Tali; Pankov, Aleksandr; Johnson, Brett E et al. (2015) DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. Cancer Cell 28:307-17
Prados, Michael D; Byron, Sara A; Tran, Nhan L et al. (2015) Toward precision medicine in glioblastoma: the promise and the challenges. Neuro Oncol 17:1051-63
Swartling, Fredrik J; Bolin, Sara; Phillips, Joanna J et al. (2014) Signals that regulate the oncogenic fate of neural stem cells and progenitors. Exp Neurol 260:56-68
Davies, Jason M; Robinson, Aaron E; Cowdrey, Cynthia et al. (2014) Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma. J Neurosurg 120:331-6

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