Underlying any future chemotherapeutic advances in the treatment of malignant gliomas will be a further understanding of the intracellular mechanisms of growth regulation. Recent work suggests that the Protein Kinase C (PKC) signal transduction system may function as a dominant regulator of proliferation of malignant gliomas in vitro. These tumor cells possess very high intrinsic PKC activity in comparison to non- transformed glia, and this high activity correlates strongly with their proliferation rates in vitro. This high activity offers a potential target for chemotherapeutic inhibition in these tumors. The central theme of the present proposal will explore the molecular basis of PKC activity within these tumors, with direct clinical extrapolation of the work being to test the utility of targeting PKC activity for growth inhibition of gliomas in vivo. Such a proposal spans a Spectrum of investigation from molecular biology to clinical studies. The preliminary objective of the proposal will examine the molecular basis for the high PKC activity, which may represent a genetic alteration in the PKC System itself, or may reflect the enzyme being driven by up-regulated growth factor systems known to exist in these tumors. To differentiate these possibilities, analysis of the PKC isozymes in gliomas will be performed at the protein (western blotting and flow cytometry), mRNA (northern blotting), and DNA (Southern blot) levels. As an extension of pre-clinical studies, inhibitors of PKC will be utilized in rat glioma model to study chemotherapeutic potential in vivo; preliminary work has demonstrated that such inhibitors may extend survival in this model. Optimal routes of administration and dosing kinetics must be established. Further pre-clinical animal studies will be the utilization of gene therapy to target specific overexpressed PKC isozyme activity in the malignant glioma cell. In addition to further experience with molecular biological techniques, this phase will represent a major developmental component for the applicant. The clinical correlate of the work is an ongoing study administering high dose Tamoxifen (which inhibits PKC, a property distinct from estrogen receptor blockade) to patients harboring recurrent malignant gliomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001672-03
Application #
2259722
Study Section
NST-2 Subcommittee (NST)
Project Start
1993-09-01
Project End
1998-08-31
Budget Start
1995-09-22
Budget End
1996-08-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Southern California
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Simard, Marie; Arcuino, Gregory; Takano, Takahiro et al. (2003) Signaling at the gliovascular interface. J Neurosci 23:9254-62
Zhang, Wei; Nwagwu, Chiedozie; Le, Duc Minh et al. (2003) Increased invasive capacity of connexin43-overexpressing malignant glioma cells. J Neurosurg 99:1039-46
Simard, Marie; Zhang, Wei; Hinton, David R et al. (2002) Tamoxifen-induced growth arrest and apoptosis in pituitary tumor cells in vitro via a protein kinase C-independent pathway. Cancer Lett 185:131-8
Spiller, M; Tenner, M S; Couldwell, W T (2001) Effect of absorbable topical hemostatic agents on the relaxation time of blood: an in vitro study with implications for postoperative magnetic resonance imaging. J Neurosurg 95:687-93
Zhang, W; Couldwell, W T; Song, H et al. (2000) Tamoxifen-induced enhancement of calcium signaling in glioma and MCF-7 breast cancer cells. Cancer Res 60:5395-400
Zhang, W; Couldwell, W T; Simard, M F et al. (1999) Direct gap junction communication between malignant glioma cells and astrocytes. Cancer Res 59:1994-2003
Zhang, W; Law, R E; Hinton, D R et al. (1997) Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. Cancer Lett 120:31-8
Couldwell, W T; Law, R E; Hinton, D R et al. (1996) Protein kinase C and growth regulation of pituitary adenomas. Acta Neurochir Suppl 65:22-6
Zhang, W; Hinton, D R; Surnock, A A et al. (1996) Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen, and hypericin: corroborating clinical response in vitro: case report. Neurosurgery 38:587-90;discussion 590-1
Couldwell, W T; Hinton, D R; Surnock, A A et al. (1996) Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 2:619-22

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