Reprogramming the Tumor Microenvironment to Improve Hearing and Treatment Efficacy in NF2 Vestibular Schwannoma
Abstract
This proposal addresses the 2019 Neurofibromatosis Research Program Emphasis Areas of “Target identification, drug discovery.” Neurofibromatosis type II (NF2) is a disease that needs new solutions. The hallmark of NF2 is bilateral vestibular schwannomas (VS), which progressively enlarge, leading to sensorineural hearing loss that translates to social impairment and clinical depression. No drug is Food and Drug Administration (FDA)-approved to treat VS or the associated hearing loss. Treatment with bevacizumab improves hearing in some patients. However, not all NF2 patients with hearing loss respond to bevacizumab, and even in those that respond, the effect is not durable. Radiation therapy is one of the main standard treatments of growing VS. However, radiation can further damage the nerve and aggravate hearing loss. The development of a novel therapy with enhanced efficacy and minimized toxicity-related hearing loss in VS is urgently needed. The greatest barrier to managing NF2-related hearing loss is our poor understanding of how schwannomas cause auditory impairment. A previous study showed that hemorrhage-related fibrosis exists in the schwannomas and correlates with hearing loss. Fibrosis is the formation of excess extracellular matrix molecules in the tissue; the fibrotic content leads to a buildup of compressive forces that induce vessel collapse, hypoperfusion, and poor delivery of oxygen and drugs. Fibrosis is also a well-characterized result of radiation-induced tissue damage. Whether reducing baseline and radiation-induce fibrosis can rescue hearing function is not known. In our preliminary studies, we confirmed the presence of fibrosis in human VS. We have recently established a novel cerebellopontine angle mouse model that faithfully reproduces schwannoma-induced hearing loss. Using this animal model, we reproduced the radiation-induced fibrosis in mice. Furthermore, we showed evidence that treatment with losartan, one of the most frequently prescribed, FDA-approved, antihypertensive drugs, which blocks fibrogenic angiotensin signaling, reduced schwannoma fibrosis and rescued hearing function. Based on the compelling preliminary evidence from clinical studies and experiments in animal models, our goal here is to evaluate the potential of losartan to (1) rescue hearing and (2) enhance the efficacy and (3) lower the required dose of radiation therapy, which can further preserve hearing function in schwannomas. Our overarching hypothesis is that the anti-fibrotic losartan, via depleting fibrosis, will normalize the tumor microenvironment to reduce inflammation and improve hearing function, enhance the efficacy and help lower the dose of radiation, and preserve hearing function in schwannomas. Potential Impact: The successful implementation of our project will fill a gap in the NF2 research field and could lead to a new translatable therapeutic strategy to reduce the radiation dose and preserve hearing for VS patients. The results of our study have provided the rationale for combining losartan with radiation in VS clinical studies. Based on our compelling data, Dr. Helen Shih has amended the current ongoing clinical trial (NCT01199978) to include 10 patients to be treated with losartan concurrently with fractionated proton therapy (see Letter of Support), with follow-up evaluations for hearing function. In addition, we will identify biomarkers of response to treatment in patient samples to help devise individualized plans for patients and to provide the best possible care based on their unique needs. As one of the most commonly prescribed drugs for hypertension, the safety and low cost (less than $1/day) of losartan warrants rapid translation of our research to patients with VS-induced sensorineural hearing loss. If successful, this project will provide in the short term a new therapeutic strategy that could be implemented in any Cancer Center in the United States (including Depart
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010222
Entities
People
- Lei Xu
Organizations
- Massachusetts General Hospital
- United States Army