The Rationale for the Proposed Work: Neurofibromatosis type 2 (NF2) is a debilitating disorder that causes substantial suffering and premature death due to tumors that occur at multiple locations in the body throughout a person's life. The hallmark finding of NF2 is the presence of bilateral vestibular schwannomas (VSs), also called acoustic neuromas, which arise from the balance nerves. VSs can cause disabling problems, including hearing loss, tinnitus, balance disturbances, and facial paralysis. As these tumors grow, they can cause fluid pressure on the brain and even death from brainstem compression. We focus on VSs because they are characteristic of NF2, and patients find deafness and facial paralysis due to VSs particularly disabling.
Current treatments for VSs are largely limited to surgery and radiation therapy. Surgery carries substantial risks, including deafness and facial paralysis. Radiation can be associated with severe side effects such as further hearing and balance loss and potential cancer formation in the radiated area.
Development of drugs for VS and NF2 has been largely unsuccessful, and no drug is Food and Drug Administration (FDA)-approved to treat this disease. Recent clinical trials for NF2 have involved small numbers of patients and expensive drugs that can cause severe side effects, such as kidney failure. Therefore, there is an unmet medical need for effective and affordable drugs for NF2 and VS. We propose to address that need by testing the efficacy of aspirin to prevent VS growth. We focus on aspirin based on our laboratory studies of schwannoma cells suggesting that aspirin can decrease the growth of VS cells, our previous pilot study that showed that the likelihood of VS growth was reduced in people taking aspirin for unrelated medical reasons, and others' data that aspirin decreases schwannoma progression in an animal model of NF2.
Objective: Our main objective is to determine whether aspirin prevents VS growth. To reach that objective, we propose a prospective, randomized, placebo-controlled, Phase 2 trial of aspirin for VSs. Our secondary objective is to determine whether changes in levels of certain proteins in the blood predict and reflect changes in VS growth and/or hearing due to aspirin treatment.
To maximize the number of potential subjects and achieve the objective of our study, we will investigate VSs that occur in association with NF2 or in patients without NF2 (sporadic VS). Sporadic and NF2-associated VSs are similar genetically, histologically, and clinically. By studying them together, we can speed discoveries of new therapies for NF2 and VS because sporadic VSs are at least three to five times more common than NF2-associated VSs. We aim to recruit 300 patients who will be equally split into two groups: a group receiving aspirin or a group receiving a non-aspirin look alike (i.e., "sugar pill") placebo. As such, this will be the largest prospective clinical study of VS patients undergoing a drug treatment.
The Ultimate Applicability and Impact of the Research: Our work will help patients with NF2 and sporadic VSs by evaluating a potential new, safe, and affordable drug to prevent VS growth. Since VSs are non-cancerous, preventing VS growth can be helpful, even without killing tumor cells. Aspirin is a commonly used, inexpensive, FDA-approved anti-inflammatory medication with minimal side effects compared to the expensive, investigational drugs with potentially serious side effects that have been used in small clinical trials for NF2 thus far. Importantly, aspirin is known to provide some protection against growth, although not curative, in multiple types of human cancer, including colon, gastric, breast, and prostate cancer. Those results and our pilot data breed confidence in the success of the proposed clinical trial. By studying a large number of patients using imaging, hearing tests, and checking proteins in the blood across six clinical sites participating in the study, we hope to identify predictors of a favorable response to therapy. Our results may enable a personalized medicine approach in which future VSs patients can be identified who will respond to aspirin. By bringing a new perspective to the NF field, while exploring an FDA-approved drug, we hope to stimulate and expedite improved treatments for VSs and NF2.