Anti-angiogenic therapy holds much promise for the treatment of malignancies like glioblastoma (GBM), a devastating brain cancer for which effective treatments are badly needed. Based on encouraging clinical trial results, in 2009, the anti-angiogenic VEGF-neutralizing antibody bevacizumab was granted accelerated FDA approval for recurrent GBM treatment. However, while the initial responses to anti-angiogenic therapy are often significant, subsequent randomized trials have shown that these agents have limited durations of response. Many tumors, after responding initially, develop acquired invasive resistance, a rapidly progressive state with a poor prognosis. Mouse models suggest that resistance to anti-angiogenic therapy likely reflects post- transcriptional protein modifications that are more readily generated than the mutations that cause traditional chemotherapy resistance. Along these lines, during the past four years of funding, we have shown that bevacizumab-induced VEGF depletion causes GBM cells to release receptor tyrosine kinase c-Met and ?1 integrin from VEGFR2 sequestration, enabling these two receptors to form a powerful structural complex in which c-Met displaces ?5 integrin from its ?1 binding site due to greater affinity and the c-Met/?1 complex exhibits increased affinity than ?5?1 integrin for fibronectin. To advance these findings, the goal of this grant renewal is to investigate the hypothesis that invasive resistance to anti-angiogenic therapy can be overcome by targeting the interaction between c-Met and ?1 integrin. We will investigate this hypothesis within the following Specific Aims:
Aim 1 - Investigate mechanisms by which VEGF depletion drives c-Met/?1 complex- mediated invasiveness in bevacizumab-resistant GBM;
Aim 2 ? Determine if the c-Met/?1 complex gives rise to specific cytoskeletal changes that drive invasive bevacizumab resistance in GBM;
and Aim 3 - Identify therapies that inhibit the binding of c-Met and ?1 integrin in bevacizumab-resistant GBM. We will carry out these studies using unique tools and innovations developed in my lab, including our novel in vivo models of anti-angiogenic therapy resistance, along with 3D bioengineered systems for studies of tumor cell invasion and small molecule inhibitor libraries created by our collaborators. These tools will be analyzed using the latest techniques, including CRISPR gene editing and mass spectrometry-based immuno-precipitation proteomics to assess the impact of c-Met-?1 binding. Successful completion of this project would define central mechanisms of resistance to anti-angiogenic therapy driven by prolonged VEGF depletion reversing the normal invasion suppressing effects of VEGF and would identify agents targeting invasive resistance to anti-angiogenic therapy. Therefore, we expect these studies to offer insight into the double-edged sword of anti-angiogenic therapy by revealing adverse effects of prolonged VEGF blockade, and could ultimately allow anti-angiogenic therapy to fulfill its tremendous therapeutic promise.

Public Health Relevance

While much heralded, the arrival of angiogenesis inhibitors into the clinic, in particular ones targeting the VEGF pathway, has unfortunately been associated with mostly transitory responses followed by renewed tumor progression, typically of an invasive nature. The renewal of this project will focus on the hypothesis that invasive resistance to anti-angiogenic therapy can be overcome by preventing the interaction between c-Met and ?1 integrin. Verification of this hypothesis would pave the way for targeting resistance to anti-angiogenic therapy before it leads to untreatable tumor growth, potentially restoring the therapeutic promise once held by anti-angiogenic therapies and offering the improved survival that patients with malignancies like glioblastoma desperately need.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079697-07
Application #
9781772
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Fountain, Jane W
Project Start
2013-09-30
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Jahangiri, Arman; Nguyen, Alan; Chandra, Ankush et al. (2017) Cross-activating c-Met/?1 integrin complex drives metastasis and invasive resistance in cancer. Proc Natl Acad Sci U S A 114:E8685-E8694
Castro, B A; Flanigan, P; Jahangiri, A et al. (2017) Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy. Oncogene 36:3749-3759
Jahangiri, Arman; Chin, Aaron T; Flanigan, Patrick M et al. (2017) Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. J Neurosurg 126:191-200
Kuang, Ruby; Jahangiri, Arman; Mascharak, Smita et al. (2017) GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance. JCI Insight 2:e88815
Yagnik, Garima; Jahangiri, Arman; Chen, Rebecca et al. (2017) Role of a p53 polymorphism in the development of nonfunctional pituitary adenomas. Mol Cell Endocrinol 446:81-90
Kwiatkowski, Sam C; Guerrero, Paola A; Hirota, Shinya et al. (2017) Neuropilin-1 modulates TGF? signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy. PLoS One 12:e0185065
Müller, Sören; Kohanbash, Gary; Liu, S John et al. (2017) Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol 18:234
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Barajas Jr, Ramon F; Butowski, Nicholas A; Phillips, Joanna J et al. (2016) The Development of Reduced Diffusion Following Bevacizumab Therapy Identifies Regions of Recurrent Disease in Patients with High-grade Glioma. Acad Radiol 23:1073-82

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