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.
|Peterson, Teresa E; Kirkpatrick, Nathaniel D; Huang, Yuhui et al. (2016) Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci U S A 113:4470-5|
|Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh et al. (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 113:4476-81|
|Flavahan, William A; Drier, Yotam; Liau, Brian B et al. (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110-4|
|Curry Jr, William T; Gorrepati, Ramana; Piesche, Matthias et al. (2016) Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma. Clin Cancer Res 22:2885-96|
|Stevens, Mark M; Maire, Cecile L; Chou, Nigel et al. (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34:1161-1167|
|Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane et al. (2016) Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clin Cancer Res 22:1185-96|
|Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6|
|Tateishi, Kensuke; Iafrate, A John; Ho, Quan et al. (2016) Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma. Clin Cancer Res 22:4452-65|
|Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen et al. (2016) Rac1-mediated membrane raft localization of PI3K/p110Î² is required for its activation by GPCRs or PTEN loss. Elife 5:|
|Fathi, Amir T; Nahed, Brian V; Wander, Seth A et al. (2016) Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma. Oncologist 21:214-9|
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