Preclinical Validation of Anti-Nuclear Factor Kappa B Therapy against Vestibular Schwannoma and Neurofibromatosis Type II.

摘要

Neurofibromatosis type 2 (NF2) is a genetic disorder that causes substantial suffering and debility due to many tumors that occur on the nerves within the skull and spine throughout a person's life. The hallmark of NF2 is vestibular schwannomas (VSs), also known as acoustic neuromas, which occur on the vestibular nerves that connect the inner ear with the brain. Initially, VSs cause hearing loss. However, as they grow, they can compress the brainstem and cause death. Current treatment options are limited to surgical removal and radiation therapy, both of which carry substantial risks, including deafness and facial paralysis. Although drug therapies against NF2 are gaining momentum, more effective and better tolerated drugs are sorely needed. Because NF2 tumors are typically slowly growing and non-malignant, even therapies that simply reduce tumor volume and retard growth can be lifesaving. The most successful drug used today to treat NF2, bevacizumab, works in only about 50% of patients in halting tumor growth or causing tumor shrinkage. Bevacizumab is known to inhibit vascular endothelial growth factor (VEGF), but its precise mechanism of action in VSs is unknown. Our overriding objective it to develop new and better drug therapies to help people with NF2. Using an unbiased bioinformatic approach that synthesizes published knowledge on the genes that are known to be aberrantly expressed in NF2, we have identified a key role for nuclear factor kappa B (NF Kappa B ). We hypothesize that increased NF B signaling in VS contributes to abnormal growth, and that inhibition of the NF Kappa B pathway can prevent growth and promote death of VSs. We have proven this hypothesis in vitro, using primary human VS cells treated with 3 different NF kappa B inhibitors: (1) shRNA, (2) an experimental drug, BAY11, and (3) a dietary supplement, curcumin.