Two companion papers from Massachusetts General Hospital (MGH) research teams suggest that targeting multiple angiogenesis pathways simultaneously could help overcome the resistance to anti-angiogenic treatment inevitably developed by the devastating brain tumour glioblastoma.

Appearing in PNAS Early Edition, the reports describe how two different methods of inhibiting both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in animal models not only normalised tumour blood vessels to a greater extent than anti-VEGF therapy alone but also shifted the action of tumour-infiltrating immune cells from a pro-tumour to an anti-tumour state.

"These papers offer a potential solution for glioblastoma's escape from anti-VEGF therapy, which is mediated by activating alternative growth factor pathways," says Rakesh K. Jain, PhD, director of the Steele Laboratory of Tumour Biology in the MGH Radiation Oncology Department and co-corresponding author of both papers.

"In our back-to-back papers we not only provide proof-of-principle data that dual treatment strategies can slow glioblastoma growth and improve survival but also reveal the underlying mechanisms for these benefits."

The most common malignant tumour arising in the brain, glioblastoma is characterised by a highly abnormal, leaky and inefficient blood supply, caused by the overexpression of angiogenic factors like VEGF.

These vascular abnormalities lead to swelling around the tumour and poor blood perfusion within the tumour, causing it to become more aggressive and resistant to chemotherapy and radiation treatment.

While anti-VEGF treatment has become part of standard postsurgical treatment for glioblastoma, its beneficial effects are temporary and do not extend patient survival.

Previous studies from members of these MGH teams revealed that glioblastoma patients receiving anti-VEGF treatment also had a transient drop in blood levels of Ang-2.

Levels of that factor rebounded as tumour progression resumed, suggesting that Ang-2 activity may contribute to resistance to anti-VEGF treatment.

The researchers also found that, similar to VEGF, Ang-2 is expressed by all types of glioblastomas. To capture the diversity of different glioblastoma types, the investigators designed two methods of testing whether inhibiting both pathways could overcome treatment resistance.

One approach combined the use of the experimental oral anti-VEGF drug cediranib with an Ang-2-neutralising antibody in two mouse models of glioblastoma and found that dual therapy improved blood vessel normalisation and extended survival compared with cediranib treatment alone.

Dual therapy also attracted tumour-associated macrophages (TAMs) to the tumours and increased the proportion of the anti-tumour form of those immune cells.

Importantly, blocking the migration of TAMs to tumours reduced the benefits of dual therapy.

The second study used an antibody that targets both VEGF and Ang-2 and showed that dual treatment improved the architecture of tumour vessels in a mouse model with abnormal vessels.

TAMs were reprogrammed to an anti-tumour state in both this tumour model and in another model not characterised by abnormal vasculature, indicating that vascular normalisation was not the only mechanism of benefit.

In fact, dual therapy promoted anti-tumour immunity by shifting the population of TAMs towards an anti-tumour form, consistent with the first study but regardless of whether or not surrounding blood vessels were abnormal.

"Our studies indicate that dual targeting of VEGF and Ang-2 could overcome some of the shortcomings of currently available glioblastoma therapies," says Jain, who is the Andrew Werk Cook Professor of Tumour Biology at Harvard Medical School.

"Clinically accessible agents are currently available for this dual targeting strategy, and our finding that dual therapy can also improve anti-tumour immune responses, irrespective of its effect on blood vessels, is particularly timely given the rapid development of new immunotherapies. These results open new avenues of research on novel combinations to obtain more durable results against this devastating disease."

Articles : DOI 10.1073/pnas.1525349113 and 10.1073/pnas.1525360113