# Tumor cell and microenvironment changes causing antiangiogenic therapy resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $351,943

## Abstract

PROJECT SUMMARY
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 β1
integrin from VEGFR2 sequestration, enabling these two receptors to form a powerful structural complex in
which c-Met displaces α5 integrin from its β1 binding site due to greater affinity and the c-Met/β1 complex
exhibits increased affinity than α5β1 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 β1 integrin. We will investigate this hypothesis within the
following Specific Aims: Aim 1 - Investigate mechanisms by which VEGF depletion drives c-Met/β1 complex-
mediated invasiveness in bevacizumab-resistant GBM; Aim 2 – Determine if the c-Met/β1 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 β1 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-β1 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 a...

## Key facts

- **NIH application ID:** 9973086
- **Project number:** 5R01NS079697-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Manish Aghi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,943
- **Award type:** 5
- **Project period:** 2013-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973086

## Citation

> US National Institutes of Health, RePORTER application 9973086, Tumor cell and microenvironment changes causing antiangiogenic therapy resistance (5R01NS079697-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973086. Licensed CC0.

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