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 became just the third FDA-approved treatment for GBM in the past four decades. However, while the initial responses to anti-angiogenic therapy are often significant, these agents have had 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 transcriptional or translational changes that are more readily generated than the mutations that typically arise with traditional chemotherapy resistance. The goal of this application is to investigate the hypothesis that invasive anti-angiogenic therapy resistance is mediated by an interaction between upregulated receptor tyrosine kinase c-Met and 1 integrin, and that targeting these two factors or their upstream regulators can prevent or overcome therapeutic resistance. We will investigate this hypothesis within the following Specific Aims:
Aim 1 - Determine the mechanisms by which chemotactic c-Met and haptotactic 1 integrin are upregulated following anti-angiogenic therapy;
Aim 2 - Examine the mechanisms by which c-Met and 1 integrin interact to promote invasion and growth of tumors resistant to anti-angiogenic therapy;
and Aim 3 - Investigate the impact of disrupting c-Met and 1 integrin or their regulators on the in vivo invasive growth of tumors during anti-angiogenic therapy or after acquired resistance. We will carry out these studies using unique tools and innovations developed in my lab, including novel in vivo models of anti-angiogenic therapy resistance and an innovative application of fluorescence recovery after photobleaching (FRAP) to correlate integrin mobility and turnover in focal adhesions with drug resistance. Successful completion of this project could (1) define the effects of VEGF on tumor invasion; (2) define central mechanisms of resistance to anti-angiogenic therapy, which would also help us understand how tumors adapt to hypoxia in general; and (3) 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 devascularization or VEGF blockade, and could ultimately allow anti-angiogenic therapy to fulfill its tremendous therapeutic promise.
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. This project will focus on the hypothesis that invasive anti-angiogenic therapy resistance is mediated by an interaction between upregulated receptor tyrosine kinase c- Met and 1 integrin, and that targeting these two factors or their upstream regulators can prevent or overcome therapeutic resistance. 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.
|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|
|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|
|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|
|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|
|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|
|Han, Seunggu J; Bankiewicz, Krystof; Butowski, Nicholas A et al. (2016) Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system. Expert Rev Neurother 16:635-9|
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