Advisory Committee Chair
Advisory Committee Members
Louis B Nabors
Danny R Welch
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
Thrombospondin-1 (TSP-1) is a 420 kilodalton homotrimeric protein; it is one of the first identified anti-angiogenic proteins found to be expressed in some normal tissues. Peptides derived from the type-1 repeat (TSR) domains of full length TSP-1 have been shown to have anti-angiogenic activity, and thus anti-tumor activity in some non-glioma tumor models. I hypothesized that peptides derived from the TSRs of TSP-1, such as ABT-510, could inhibit angiogenesis and thus malignant glioma tumor growth in vivo. I found that ABT-510 inhibited angiogenesis of the human brain microvascular endothelial cell (MvEC) in an in vitro tubulomorphogenesis assay. To determine the mechanism of this inhibition of angiogenesis by ABT-510, I measured the levels of pro-apoptotic signaling molecules. I found that ABT-510 induced caspase-dependent apoptosis of the human brain MvEC propagated as a monolayer, as well as inhibited tubulomorphogenesis in a caspase-dependent manner. Furthermore, ABT-510’s inhibition of tubulomorphogenesis required CD36, a known receptor for TSP-1.To test the role of the tumor microenvironment in this pro-apoptotic signaling I plated the brain MvEC on different substrates and found a differential induction of apoptosis depending on the matrix on which they were plated. This supports the concept that tumor associated MvEC can be targeted preferentially, and is supported by the observation of multiple other investigators that the matrix (basement membrane) of endothelial cells (EC) in tumor vessels is altered. I then tested the effectiveness of ABT-510 iii as an anti-angiogenic agent in vivo using two orthotopic models of malignant glioma; one a syngeneic mouse tumor model; and one a xenograft human tumor/mouse host model. ABT-510 treatment resulted in a significant decrease in angiogenesis in both tumor models, and a significant decrease in tumor growth. The anti-angiogenic effect of ABT-510 appeared to be through an increase in apoptotic MvEC within the tumor. These data suggest that ABT-510 is an effective anti-angiogenic agent in vitro and in vivo, and should lead to clinical trials of TSP-1 TSR peptides, likely as part of a combination therapy, in the treatment of patients with malignant glioma.
Anderson, Joshua C., "Thrombospondin Type-1 Repeats and Their Potential Role in Inhibiting Glioblastoma Angiogenesis" (2008). All ETDs from UAB. 253.