Angiogenesis is critical for the development and maintenance of glioblastomas, the most malignant and most common form of primary brain tumors. Current evidence indicates that recruitment of tumor vessels from normal surrounding tissue, and development and maintenance of tumor angiogenesis require a delicate balance between the timing and level of expression of two major angiogenesis factors: Angiopoietin-2 (Ang-2) and the vascular endothelial growth factor-A (VEGF-A). The combination of Ang-2 and VEGF-A expressions results in loosening of peri-endothelial support rendering the newly exposed endothelial cells able to multiply. We hypothesize that there is a regulatory signaling loop involving the coordinated and sequential expression of VEGF and Ang-2, and that elucidating the underlying mechanisms can lead to developing a better model for the angiogenic process that occurs in human gliomas. Importantly, we have uncovered the expression of Tie2 in glioma cells. Moreover, exploiting the interdependence between VEGFand Ang-2 could be used to develop more effective and rational anti-angiogenesis therapies for brain tumors than currently exist. Therefore, in this application we shall aim to uncover the mechanisms of interaction between Ang-2 and VEGF-A, the role of Ang-2 expression in a dynamic tumor model of glioma angiogenesis, and to develop an effective treatment based on the simultaneous targeting of Ang-2, using conditionally-replicative adenoviruses, and direct down modulation of VEGF using antisense strategies.
The specific aims are as follows:
Specific Aim 1 : To characterize the modulation of VEGF-A by Ang-2;
Specific Aim 2 : To determine the effects of Angiopoietin-2 on the growth kinetics and angiogenesis development in a glioma model;
and Specific Aim 3 : To examine the anti-glioma effect of combined therapies based on the transfer of Angiopoietin-2, using oncolytic adenoviruses, and anti-sense VEGF. This project should yield important mechanistic information about the abnormal regulation of angiogenesis in gliomas. Furthermore, data obtained from our studies will hopefully constitute a rational basis for the development of a Phase 1/11clinical trial to test the toxicity and efficacy of a triple treatment for malignant gliomas, which combines the overexpression of Ang-2, decreased VEGF expression, and oncolysis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA083127-04A2
Application #
6870880
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2000-03-01
Project End
2008-08-31
Budget Start
2004-09-22
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$251,038
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lee, O-H; Xu, J; Fueyo, J et al. (2008) Angiopoietin-2 decreases vascular endothelial growth factor expression by modulating HIF-1 alpha levels in gliomas. Oncogene 27:1310-4
Gomez-Manzano, Candelaria; Fueyo, Juan; Jiang, Hong et al. (2003) Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann Neurol 53:109-17
Gomez-Manzano, C; Mitlianga, P; Fueyo, J et al. (2001) Transfer of E2F-1 to human glioma cells results in transcriptional up-regulation of Bcl-2. Cancer Res 61:6693-7