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.
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.
|Zhao, Yingchao; Liu, Pinan; Zhang, Na et al. (2018) Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. Proc Natl Acad Sci U S A 115:E2077-E2084|
|Bian, X; Gao, J; Luo, F et al. (2018) PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene 37:341-351|
|McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25|
|McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804|
|Shankar, Ganesh M; Kirtane, Ameya R; Miller, Julie J et al. (2018) Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A 115:E8388-E8394|
|Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726|
|Li, Ben B; Qian, Changli; Roberts, Thomas M et al. (2018) Targeted Profiling of RNA Translation. Curr Protoc Mol Biol :e71|
|Nowosielski, Martha; Wen, Patrick Y (2018) Imaging Criteria in Neuro-oncology. Semin Neurol 38:24-31|
|Li, Ben B; Qian, Changli; Gameiro, Paulo A et al. (2018) Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A 115:E9325-E9332|
|Khandekar, Melin J; Jain, Rakesh (2018) Smooth sailing for immunotherapy for unresectable stage III non-small cell lung cancer: the PACIFIC study. Transl Cancer Res 7:S16-S20|
Showing the most recent 10 out of 84 publications