A pathophysiological hallmark of glioblastoma (GBM) is the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic cytokines, which, in turn, stimulate endothelial cell proliferation, migration and survival. The result is a highly abnormal tumor vascular network that promotes tumor growth and may impair the efficacy of cytotoxic therapies by enhancing tumor hypoxia and impairing drug delivery. The mechanism of action of anti-VEGF therapies is incompletely understood. The """"""""classical"""""""" view is that anti-VEGF therapy decreases tumor vessel perfusion and """"""""starves"""""""" the tumor of oxygen and essential nutrients. In contrast, the vascular normalization hypothesis holds that anti-VEGF therapy enhances chemo radiation by transiently normalizing tumor blood vessels, reducing hypoxia and improving chemotherapy delivery. Based on our preclinical and clinical studies of different anti-VEGF therapeutics across multiple solid tumor subtypes, including GBM, we hypothesize that anti-VEGF therapies achieve clinical benefit by transiently normalizing tumor blood vessels. Bevacizumab, a humanized, monoclonal antibody against the VEGF-A ligand, was approved as monotherapy for recurrent GBM (rGBM) in 2009. However, responses to bevacizumab are variable, most responses are not durable and the mechanism of action in GBM is not established. To date, no reliable imaging or biospecimen markers of tumor response versus resistance to bevacizumab exist and this expensive and potentially toxic therapy is administered to all rGBM patients. Based on our preclinical studies using orthotopic GBM models and our findings in newly diagnosed GBM (nGBM) and rGBM patients treated with the pan-VEGF receptor tyrosine kinase inhibitor, cediranib, we advance the following hypotheses: 1) Bevacizumab achieves maximal therapeutic benefit in a subset of GBM patients by transient normalization of tumor vessels leading to alleviation of brain edema, reduction in tumor hypoxia and enhanced delivery of temozolomide;2) Imaging and biospecimen markers of vascular normalization are useful in the identification of responsive versus resistant GBM subpopulations;3) Bevacizumab resistance develops due to the activation of alternative pro-angiogenic or pro-invasive signal transduction pathways. In this competing renewal application, we build on our observations in GBM patients treated with cediranib and extend and expand these studies to patients treated with bevacizumab, the only approved anti-VEGF therapeutic for GBM. We will analyze biospecimen and imaging markers of response versus resistance in the rGBM patient population with an emphasis on vascular normalization and how the latter impacts the hypoxic tumor microenvironment, chemotherapy delivery and tumor cell proliferation.

Public Health Relevance

Glioblastoma is a highly lethal form of brain cancer that is dependent on the formation of tumor blood vessels for growth and invasion. Although therapies that target these tumor blood vessels are being developed only some glioblastoma patients have lasting responses to these anti-angiogenic treatments. Building on promising data from our earlier studies, the primary goals of this project are to define non-invasive radiological and blood markers that identify the group of glioblastoma patients most likely to benefit from anti-angiogenic treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Clinical Oncology Study Section (CONC)
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Henderson, Lori A
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Massachusetts General Hospital
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Han, Catherine H; Batchelor, Tracy T (2017) Primary Central Nervous System Lymphoma. Continuum (Minneap Minn) 23:1601-1618
Wang, Nancy; Jain, Rakesh K; Batchelor, Tracy T (2017) New Directions in Anti-Angiogenic Therapy for Glioblastoma. Neurotherapeutics 14:321-332
Ellingson, Benjamin M; Gerstner, Elizabeth R; Smits, Marion et al. (2017) Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials. Clin Cancer Res 23:5745-5756
Andronesi, Ovidiu C; Esmaeili, Morteza; Borra, Ronald J H et al. (2017) Early changes in glioblastoma metabolism measured by MR spectroscopic imaging during combination of anti-angiogenic cediranib and chemoradiation therapy are associated with survival. NPJ Precis Oncol 1:
Andronesi, Ovidiu C; Loebel, Franziska; Bogner, Wolfgang et al. (2016) Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate. Clin Cancer Res 22:1632-41
Ohnishi, Takashi; Nakamura, Yuka; Tanaka, Toru et al. (2016) Deformable image registration between pathological images and MR image via an optical macro image. Pathol Res Pract 212:927-936
Gerstner, Elizabeth R; Ye, Xiaobu; Duda, Dan G et al. (2015) A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro Oncol 17:1386-92
Prust, Morgan J; Jafari-Khouzani, Kourosh; Kalpathy-Cramer, Jayashree et al. (2015) Standard chemoradiation for glioblastoma results in progressive brain volume loss. Neurology 85:683-91
Jafari-Khouzani, Kourosh; Emblem, Kyrre E; Kalpathy-Cramer, Jayashree et al. (2015) Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. Transl Oncol 8:137-46
Lu-Emerson, Christine; Duda, Dan G; Emblem, Kyrre E et al. (2015) Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 33:1197-213

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