Adding antiangiogenesis increases effectiveness of radiation against NF2-associated tumors

Adding antiangiogenesis increases effectiveness of radiation against NF2-associated tumors

Investigators report in PNAS that use of an antiangiogenesis drug reduced the radiation dose required to shrink tumors in animal models of the NF2-associated tumors called vestibular schwannomas. They also discovered several mechanisms behind this effect and determined the time window during which radiation therapy produces the best results in the tested model.

NF2 is characterized by benign tumors that develop throughout the nervous system. The most common site of these tumors is the eighth cranial nerve, which carries hearing and balance information from the ears to the brain. Although vestibular schwannomas grow slowly, they usually lead to a significant or total hearing loss by young adulthood or middle age.

The tumors can also press on the brain stem, leading to headaches, difficulty swallowing and other serious neurologic symptoms. While the tumors can be surgically removed or destroyed with radiation treatment, both approaches can also damage hearing.

Several previous investigations had suggested that - unlike other benign tumors - vestibular schwannomas induce the formation of new blood vessels, as malignant tumors do. A 2009 New England Journal of Medicine study reported that treatment with the antiangiogenesis drug bevacizumab caused shrinkage of NF2 schwannomas in most of the treated patients and improved hearing in more than half. But the limitations of that approach - the fact that not all patients responded, that the hearing improvement was often transient and that some patients could not tolerate long-term bevacizumab treatment - indicated the need to better understand the mechanisms behind the effects of antiangiogenesis on the function of tumor-bearing nerves.

 In a series of experiments using several mouse models of nerve tumors they found that treatment with an experimental anti-VEGF drug produced more improved neurologic function than did radiation alone and that treatment reduced tissue edema, alleviating swelling that may compress nearby nerves. They also found evidence that anti-VEGF treatment enhanced the regeneration of damaged nerves and decreased atrophy in muscles connected to tumor-bearing nerves.

Careful observation of tumor vasculature in a mouse model of NF2 revealed that anti-VEGF treatment reduced the number of abnormal blood vessels within the tumor, a key mechanism behind the successful use of antiangiogenesis drugs to treat several types of cancer.

As also seen in those applications, this normalization of the tumor's blood supply proved to be temporary, beginning around day 2 of treatment and starting to diminish on day 5. Administering radiation therapy during that normalization window had significantly greater effects than did either anti-VEGF or radiation therapy alone, while radiation given outside that time had no additive effect. Giving radiation during the normalization window also increased its effectiveness, producing the same beneficial results with half the radiation dosage.