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.
|Bhawe, Kaumudi M; Aghi, Manish K (2016) Microarray Analysis in Glioblastomas. Methods Mol Biol 1375:195-206|
|Flanigan, Patrick M; Aghi, Manish K (2015) Adaptation to antiangiogenic therapy in neurological tumors. Cell Mol Life Sci 72:3069-82|
|Castro, Brandyn A; Aghi, Manish K (2014) Bevacizumab for glioblastoma: current indications, surgical implications, and future directions. Neurosurg Focus 37:E9|