Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model

Abstract

Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.NF2 schwannoma model | anti-VEGF | neurological function | radiation

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2

“…For example, in the last few years, attempts to treat NF2 with pharmacological tools have led to the discovery that the anti‐vascular antibody bevacizumab can stop the growth of tumors in many NF2 patients . In addition, an anti‐angiogenesis treatment has been described that can improve the neuropathy in a murine sciatic nerve model of NF2 . However, the effect of pharmacological treatment strategies on the NF2‐associated neuropathy in patients has not yet been described.…”

“…[8][9][10] In addition, an anti-angiogenesis treatment has been described that can improve the neuropathy in a murine sciatic nerve model of NF2. 11 However, the effect of pharmacological treatment strategies on the NF2associated neuropathy in patients has not yet been described. One reason for this may be the lack of methods suitable to quantify motor axon pathology in NF2.…”

Endoglin (CD105) expression in neurofibromatosis type 2 vestibular schwannoma

“…Anti-VEGF agents were originally developed to block tumor growth by inhibiting blood vessel formation. It has been reported more recently, however, that-in the NF2-associated VS model at least-anti-VEGF treatment does not significantly reduce VEGF production, but it does normalize the tumor vasculature and improves vessel perfusion 21 ; the end result is thus a dominant vascular effect that favors neuroprotection. The fact that not all patients respond to this treatment and that hearing improvement is often transient, combined with the lack of direct evidence of the effects of anti-VEGF treatment on nerve function, points to the need to clarify the mechanisms behind this anti-angiogenic treatment.…”

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

“…Indeed, in our schwannoma models, we found that both pharmacological and Previously, we showed that anti-VEGF treatment, via normalizing the tumor vasculature, increases tumor oxygen. Oxygen is a potent radiosensitizer; thus, combined anti-VEGF treatment enhances radiation efficacy (37). cMET activation can directly induce tumor angiogenesis by promoting endothelial cell proliferation, migration, and survival (38).…”