The purpose of the proposed project is to study the mechanisms of malignant behavior in glioma cells. We will study expression of the peripheral benzodiazepine receptor (PBR) and activation of proto-oncogenes which have been implicated in the process of glial cell oncogenesis. Our hypotheses are: 1) the malignant phenotype in glioma cells is dependent on activation of the proto-oncogene c-myc by PDGF-type signalling pathways (c-sis/PDGF-beta and Stem Cell Factor), 2) expression of the PBR, a putative marker for glial tumor cells, contributes to the malignant behavior of the cells, and 3) PBR may be expressed by the actions of these proto-oncogenes. Malignant glial tumors remain a devastating disease which responds only transiently to current therapies. Because of the selective expression of PBR by malignant glial tumors (Broaddus and Bennett, 1990), this binding site is a candidate for selectively imaging tumor cells and targeting therapies at them.
The specific aims of this project encompass plans to demonstrate localization of this component to glial tumor cells using in situ hybridization, a technique which allows much higher precision than has been used thus far in histological studies of PBR expression by tumor cells. Focussing on mechanisms of malignant transformation, we will carry out studies to show an association of changes in c-myc and PBR expression with alteration of malignant characteristics glioma cells. Finally, we propose to use antisense gene sequences to demonstrate dependence of malignant phenotype on expression of c-myc, putative autocrine growth factor systems (c-sis and SCF) and PBR. These studies will provide better understanding of the mechanisms involved in the malignant progression of glial cells, and help define the potential utility of the PBR as a target for imaging and directing cytotoxic strategies. Successful use of antisense oligonucleotide sequences to reverse glial tumor cell proliferation will also have potential applicability to gene therapy strategies.
