Project 1 is designed to improve upon the outcome of anti-angiogenic therapy in glioblastoma. The Food and Drug Administration approved bevacizumab, an anti-VEGF monoclonal antibody, as monotherapy for recurrent glioblastoma in 2009. However, the precise mechanism(s) of action of this drug in glioblastoma is not fully understood. Previously, we showed that blocking VEGF-signaling with DC101, a murine anti-VEGF antibody, or AZD2171, a pan-VEGF tyrosine kinase inhibitor, normalizes glioblastoma blood vessels and increases overall survival in animal models. However, the effects of anti-VEGF therapies on overall survival appear modest in glioblastoma patients as the tumor eventually escapes from normalization by the up regulation of other pro-angiogenic signal transduction pathways. One pro-angiogenic molecule of particular interest in this regard is angiopoietin-2 (Ang2). We have demonstrated that overexpression of Ang2 compromises the survival benefit from DC101 treatment. Moreover, Ang2 expression decreased during the vascular normalization window but increased as the tumor vessels began to become abnormal. This pattern of dynamic Ang2 expression has also been observed in the plasma of recurrent glioblastoma patients treated with AZD2171. Based on these pre-clinical and clinical data, we hypothesize that the inhibition of Ang2 may prolong the normalization window, thereby improving the clinical benefit induced by VEGF-blockade. We wiil test whether blocking both Ang2 and VEGF signaling in different schedules inhibits tumor growrth and increases overall survival in different murine glioblastoma models (Aim One). Subsequently, we will test whether blocking both of these pathways can increase survival by prolonging the normalization window over that pbserved with VEGF inhibition alone (Aim Two). Finally, we will conduct a clinical trial (Aim Three) that will assess the impact of selective Ang2 inhibition on the vascular normalization window in recurrent glioblastoma patients as well as the safety and potential efficacy of anti-Ang2 therapy. This clinical trial will provide the foundation for future combination trials of Ang2 and VEGF inhibitors, the latter informed by the results of Aims One and Two.

Public Health Relevance

Using innovative molecular and imaging approaches with pre-clinical models that simulate glioblastoma progression during anti-VEGF therapy in patients, we will define the role of the Ang2 pathway in response to VEGF inhibition. These results should provide valuable insight for future clinical trials combining anti-VEGF and anti-Ang2 agents and possibly lead to improved clinical outcomes for patients with this uniformly fatal form of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA165962-02
Application #
8932951
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Program Officer
Arnold, Julia T
Project Start
2013-09-19
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$321,988
Indirect Cost
$78,717
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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