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.
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.
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