Community Research and Development Information Service - CORDIS

FP7

ANGIOTOX Result In Brief

Project ID: 251528
Funded under: FP7-PEOPLE
Country: Ireland

Overcoming the side-effects of anti-angiogenesis therapy

Often, therapies cause unwanted side effects. Identification of the drug off-targets can help minimise toxicity and improve therapeutic outcome.
Overcoming the side-effects of anti-angiogenesis therapy
One of the hallmarks of cancer is the formation of new blood vessels, a process known as angiogenesis. Inhibition of angiogenesis is thus a promising therapeutic strategy against cancer and a number of clinically approved anti-angiogenic drugs effectively cause a reduction in tumour growth and metastasis. However, these inhibitors also have several systemic toxic side effects, limiting their effectiveness when treatment has to be withdrawn or dosing concentration decreased to alleviate toxicities.

The objective of the EU-funded ANGIOTOX (Histopathologic and mechanistic assessment of angiogenesis inhibitor related toxicities: a cross-sectoral, multi-disciplinary approach) project was to understand the mechanisms of toxicity associated with angiogenesis inhibitor treatment. In this context, histopathologic, imaging and biomarker profiling analyses was performed in pre-clinical and clinical samples.

Researchers treated rodents with clinically relevant doses of angiogenesis inhibitors and analysed their tissues via histopathology focusing on off-target cardiovascular effects. Their approach successfully recapitulated most of the common clinically observed toxicity patterns such as hypertension and compromised cardiovascular function. The latter was concomitant with alterations in cardiac metabolism as evidenced by increases in glucose and fatty acid uptake. Proteomic studies also corroborated the major metabolic aberrations that emerge following treatment with angiogenesis inhibitors. Further histopathological analysis indicated thyroid effects, skin toxicity and mild proteinuria after treatment.

Next, scientists wished to identify the targets of the anti-angiogenic inhibitors. Their analysis revealed a number of important off-target signalling proteins perturbed by treatment, which may serve as biomarkers for predicting toxicity.

Overall, the activities of the ANGIOTOX consortium provided insight into the toxicity pathways associated with angiogenesis inhibitors. The identification of novel early safety biomarkers and strategies - such as metabolic PET imaging - will help predict patients at risk of developing adverse effects whilst receiving anti-angiogenic therapy.

Related information

Keywords

Angiogenesis, toxicity, cancer, inhibitors, cardiovascular function, metabolism
Record Number: 182829 / Last updated on: 2016-05-31
Domain: Biology, Medicine