Unresectable high grade gliomas are nearly incurable in both children and adults. In fact, brain stem and mid- brain gliomas in children and GBM in adults are nearly universally fatal. The primary treatment modality for these tumors is radiotherapy with glucocorticoids with or without Temizolamide. This treatment prolongs survival but has little impact upon 5 year survival unless tumors are first resected. Recently, the enzyme autotoxin (lysophospholipase-D;LysoPLD) has been found to be over expressed in high grade gliomas. This enzyme converts lysophosphocholine (LPC) to lysophosphatetic acid (LPA) which in turn binds to LPA receptors expressed in GBM. LPA receptors are G-protein coupled receptors (GPCRs) that activate cell invasion, migration and enhance cell viability. We have recently shown that the substrate for LysoPLD, LPC, is induced by 2 Gy x-irradiation. Cytosolic phospholipase A2 (cPLA2) is activated by 2 Gy and knock down, knock out or inhibition of cPLA2 improves the cytotoxicity of ionizing radiation. We propose therefore, that the mechanism by which this signal transduction pathway improves cell viability is by conversion of LPC to LPA and subsequent LPA receptor activation. We propose that inhibition of conversion of LPC to LPA or inhibition of LPA receptors in malignant gliomas will improve outcome in this lethal disease. To test these hypotheses, we will: 1. Study the role of LysoPLD in the conversion of LPC to LPA in irradiated malignant glioma models. 2. Study the role of LPA receptors in both malignant gliomas and tumor vascular endothelium. 3. Determine whether knock down, knock out or inhibition of Lyso PLD or LPA receptors improves tumor response to ionizing radiation. These studies will help to identify novel radiation induced signal transduction pathways and potential molecular targets to improve the outcome of high grade gliomas.

Public Health Relevance

The goal of this research is to determine the role of Lysophospholipids in the radiation response in malignant gliomas. We will study the conversion of LPC to LPA and subsequent signaling through the LPA receptor in mouse glioma models and determine whether inhibitors of the LysoPLD enzyme prevents conversion to LPA. We will also determine whether inhibitors of this signaling pathway enhance the efficacy of radiotherapy in the treatment of glioblastoma models in the mouse.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140220-04
Application #
8447355
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2010-06-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$287,582
Indirect Cost
$98,383
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jiang, Xiaoyu; Engelbach, John A; Yuan, Liya et al. (2014) Anti-VEGF antibodies mitigate the development of radiation necrosis in mouse brain. Clin Cancer Res 20:2695-702
Jiang, Xiaoyu; Perez-Torres, Carlos J; Thotala, Dinesh et al. (2014) A GSK-3? inhibitor protects against radiation necrosis in mouse brain. Int J Radiat Oncol Biol Phys 89:714-21
Zhang, Yu Shrike; Cai, Xin; Yao, Junjie et al. (2014) Non-invasive and in situ characterization of the degradation of biomaterial scaffolds by volumetric photoacoustic microscopy. Angew Chem Int Ed Engl 53:184-8
Cai, Xin; Zhang, Yu Shrike; Xia, Younan et al. (2013) Photoacoustic Microscopy in Tissue Engineering. Mater Today (Kidlington) 16:67-77
Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang et al. (2013) Expression of Tax-interacting protein 1 (TIP-1) facilitates angiogenesis and tumor formation of human glioblastoma cells in nude mice. Cancer Lett 328:55-64
Laszlo, Andrei; Thotala, Dinesh; Hallahan, Dennis E (2013) Membrane phospholipids, EML4-ALK, and Hsp90 as novel targets in lung cancer treatment. Cancer J 19:238-46
Cai, Xin; Zhang, Yu; Li, Li et al. (2013) Investigation of neovascularization in three-dimensional porous scaffolds in vivo by a combination of multiscale photoacoustic microscopy and optical coherence tomography. Tissue Eng Part C Methods 19:196-204
Thotala, D K; Hallahan, D E; Yazlovitskaya, E M (2012) Glycogen synthase kinase 3ýý inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2-p53 pathway. Cell Death Differ 19:387-96
Schulte, Rachael R; Linkous, Amanda G; Hallahan, Dennis E et al. (2011) Cytosolic phospholipase A2 as a molecular target for the radiosensitization of ovarian cancer. Cancer Lett 304:137-43
Schleicher, Stephen M; Thotala, Dinesh K; Linkous, Amanda G et al. (2011) Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature. PLoS One 6:e22182

Showing the most recent 10 out of 11 publications