American Brain Tumor Association

Validation of diffusion MRI as a predictive imaging biomarker for anti-VEGF therapies in recurrent glioblastoma

The American Brain Tumor Association has announced a new Research Collaboration Grant supported by Humor to Fight the Tumor Foundation between UCLA and Massachusetts General Hospital.

The most aggressive brain tumors are those characterized by the formation of new blood vessels, or angiogenesis. Thus, treatments that target tumor angiogenesis are a viable therapeutic approach to slowing the growth of malignant gliomas and ultimately increasing survival. Randomized phase II trials have not demonstrated an overall survival (OS) benefit for all patients with recurrent glioblastoma (rGBM). There were, however, patients who experienced significant and robust responses to these therapies including a substantial improvement in survival. Thus, the current project aims to use non-invasive imaging to identify patients who will have a substantial OS benefit from anti-angiogenic therapy at first or second relapse. Our extensive preliminary data suggests diffusion MRI is a strong predictor of anti-angiogenic therapeutic efficacy, but further studies are needed to determine whether this observation is shared with other types of anti-angiogenic agents. Therefore, our first objective is to examine past clinical trial data to confirm that diffusion MRI measurements are predictive of OS in other anti-angiogenic therapies. We will then determine whether these imaging measurements and survival benefits are dependent the presence of a protein called decorin, which can be found in tumors after a biopsy, as this molecule is thought to both change the diffusion characteristics and bind to pro-angiogenic factors, potentially prolonging treatment resistance to anti-angiogenic therapies. Lastly, we will perform a prospective, multicenter clinical trial to validate the OS benefit in rGBM patients with favorable diffusion MRI measurements receiving anti-angiogenic therapies in rGBM. This project will provide important evidence for using diffusion MRI for patient selection for future anti-angiogenic therapeutic trials in rGBM.

 

Project goals and updates:

1. Utilize existing clinical trial data to confirm diffusion MR phenotypes are predictive of OS in anti-VEGF monotherapy.
   • Specific Aim was completed during this first year of funding and was published (Ellingson et al., Clin Cancer Res, 2017 Oct 1;23(19):5745-5756.)
     

      

2. Confirm the biological mechanisms responsible for diffusion MR phenotypes using stereotactic image-guided biopsies and post-mortem human specimens.
   • This aim is more than 50% complete. So far the preliminary data support the hypothesis. Additional patients are being accrued to complete the aim.
     

      

3. Prospectively verify the significant survival benefit accrued in recurrent GBM patients exhibiting a favorable diffusion MR phenotype when treated with anti-VEGF therapies in a multicenter clinical trial.
   • The proposed trial was opened and has been completed; however there are still significant analyses to be performed.