Molecular therapies for malignant glioma may have a cytostatic mechanism of action and limited toxicity. The absence of toxicity as an endpoint requires a new approach for dose-finding and efficacy testing. AlphavBeta3 antagonists have shown significant efficacy in vitro, using assays of angiogenesis and invasion. Animal studies using these agents in vivo with corneal tumor implants and orthotopic primary gliomas have also shown promising efficacy. This glioma therapy project will be similar to a Phase 2 efficacy study in patients with malignant glioma, using the primary endpoints of time-to-tumor progression (TTP) (measured clinically or radiologically) and overall survival. In this study, the efficacy of alphavBeta3 antagonists will be compared with alterations in in vivo MR tissue perfusion, permeability and vascular maturity parameters using large molecular weight contrast agents. Targeted contrast agents capable of binding specifically to the alphavBeta3 integrin will also be explored and compared with these and conventional volumetric outcomes in standard use. It is intended that these assays will allow the accurate in vivo assessment of the bio-activity and efficacy of alphavBeta3 antagonists in this model system and support the use of these imaging and bio-assay endpoints in the clinical evaluation of these agents for which conventional toxicity cannot be used for dose-finding.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA096965-01
Application #
6522090
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Liu, Guoying
Project Start
2002-07-12
Project End
2004-06-30
Budget Start
2002-07-12
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$178,750
Indirect Cost
Name
Henry Ford Health System
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Lee, Hae Kyung; Xiang, Cunli; Cazacu, Simona et al. (2008) GRP78 is overexpressed in glioblastomas and regulates glioma cell growth and apoptosis. Neuro Oncol 10:236-43
Xiang, Cunli; Sarid, Ronit; Cazacu, Simona et al. (2007) Cloning and characterization of human RTVP-1b, a novel splice variant of RTVP-1 in glioma cells. Biochem Biophys Res Commun 362:612-8
Rosenzweig, Tovit; Ziv-Av, Amotz; Xiang, Cunli et al. (2006) Related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) is overexpressed in gliomas and regulates the growth, survival, and invasion of glioma cells. Cancer Res 66:4139-48
Cao, Y; Brown, S L; Knight, R A et al. (2005) Effect of intravascular-to-extravascular water exchange on the determination of blood-to-tissue transfer constant by magnetic resonance imaging. Magn Reson Med 53:282-93
Bogler, Oliver; Mikkelsen, Tom (2005) Angiogenesis and apoptosis in glioma: two arenas for promising new therapies. J Cell Biochem 96:16-24
Bogler, Oliver; Mikkelsen, Tom (2003) Angiogenesis in glioma: molecular mechanisms and roadblocks to translation. Cancer J 9:205-13