Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit and is increasingly becoming the standard of care for patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy in a subset of patients is associated with an aggressive, diffuse, multi- focal disease recurrence pattern and a short subsequent survival interval. Using a novel primary human GBM xenograft model, we have reproduced a similar phenotype in which bevacizumab therapy results in increased glioma invasiveness and in a multi-focal disease recurrence pattern. Our preliminary data also suggest that glioma invasion is critically controlled by Src- and PI3-kinase-depedent signaling pathways. Based on these data, we hypothesize that the increased invasiveness associated with anti-VEGF therapy is due to increased signaling through these pathways. Consistent with this hypothesis, we found that the Src-family kinase (SFK) inhibitor dasatinib can prevent both the increased invasion and the multi-focal disease progression pattern induced by bevacizumab. In part based on these preliminary data, we are initiating a clinical trial testing the combination of bevacizumab and dasatinib in patients with recurrent GBM. The focus of this application is to rigorously examine the influence of SFK and PI3K signaling on the pro-invasive effects of bevacizumab both in primary GBM orthotopic xenograft models and in patients with recurrent GBM.
The specific aims are: 1. Assess the combined effects of bevacizumab and dasatinib on GBM invasion. 2. Examine the role of individual SFKs and specific downstream signaling effectors on bevacizumab-induced invasion. 3. Examine the combined effect of SFK and PI3K inhibition on GBM migration and invasiveness, and test the effects of dual inhibition on bevacizumab responsiveness.

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Anti-VEGF therapy is associated with significant prolongation in progression-free survival in patients with recurrent GBM, although ultimate disease progression on this therapy is associated with aggressive disease and a short subsequent survival interval. The focus of this application is to understand whether molecularly-targeted therapies can prevent the pro-invasive effects of anti-VEGF therapy. Ultimately this strategy may provide additional survival benefit for patients with this deadly disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Fountain, Jane W
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Mayo Clinic Jacksonville
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Kourtidis, Antonis; Anastasiadis, Panos Z (2018) Close encounters of the RNAi kind: the silencing life of the adherens junctions. Curr Opin Cell Biol 54:30-36
Kourtidis, Antonis; Necela, Brian; Lin, Wan-Hsin et al. (2017) Cadherin complexes recruit mRNAs and RISC to regulate epithelial cell signaling. J Cell Biol 216:3073-3085
Kourtidis, Antonis; Lu, Ruifeng; Pence, Lindy J et al. (2017) A central role for cadherin signaling in cancer. Exp Cell Res 358:78-85
Kourtidis, Antonis; Anastasiadis, Panos Z (2016) Bringing together cell-to-cell adhesion and miRNA biology in cancer research. Future Oncol 12:1211-4
Kourtidis, Antonis; Anastasiadis, Panos Z (2016) PLEKHA7 defines an apical junctional complex with cytoskeletal associations and miRNA-mediated growth implications. Cell Cycle 15:498-505
Fiorotto, Romina; Villani, Ambra; Kourtidis, Antonis et al. (2016) The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology 64:2118-2134
Lin, Wan-Hsin; Asmann, Yan W; Anastasiadis, Panos Z (2015) Expression of polarity genes in human cancer. Cancer Inform 14:15-28
Kourtidis, Antonis; Yanagisawa, Masahiro; Huveldt, Deborah et al. (2015) Pro-Tumorigenic Phosphorylation of p120 Catenin in Renal and Breast Cancer. PLoS One 10:e0129964
Lewis-Tuffin, Laura J; Feathers, Ryan; Hari, Priya et al. (2015) Src family kinases differentially influence glioma growth and motility. Mol Oncol 9:1783-98
Kourtidis, Antonis; Ngok, Siu P; Pulimeno, Pamela et al. (2015) Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Nat Cell Biol 17:1145-57

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