Chemoprevention for neurofibromatosis 2: just over the horizon?

See the article by Giovannini et al, on pages 493–504. Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome with a birth incidence of 1 in 25,000 to 1 in 33,000 (1). The hallmark feature of this syndrome is bilateral vestibular schwannomas which cause significant morbidity including deafness, gait failure, and disfiguring facial weakness. In newly diagnosed patients, the median time to vestibular schwannoma growth and hearing loss is 14 months and 62 months, respectively.(2) Intracranial meningiomas are also common in NF2 patients with a cumulative incidence approaching 80% by 70 years of age. (3). These tumors, along with spinal schwannomas, meningiomas, and ependymomas, can cause seizures, paraparesis, bowel/bladder dysfunction, and other neurologic dysfunction. Historically, therapeutic options for NF2 patients have been limited to surgery and radiation. However, outcomes are worse for NF2-related vestibular schwannomas than for sporadic tumors. Given the multifocal and bilateral nature of the disease, neurologic morbidity after treatment is common, and new treatment options are urgently needed. In the past few years, multiple studies of targeted agents for NF2-related tumors have been published. Inhibition of the EGFR/erbB2 pathway using erlotinib and lapatinib has been investigated based on strong preclinical data(4–6); however, clinical results using these drugs has been disappointing, with mainly transient radiographic and hearing responses.(7, 8) In contrast, retrospective studies indicate that treatment of progressive vestibular in NF2 patients using bevacizumab can result in significant improvement in hearing and radiographic responses in about 50% of patients.(9, 10) Results from completed (NCT01207687) and ongoing (NCT01767792) multicenter studies of bevacizumab are anticipated in the next few years. Finally, preclinical studies of mTOR inhibition in NF2-deficient meningioma and schwannoma lines have also documented encouraging results.(11, 12) Despite this encouraging data, a phase 2 study of the mTOR inhibitor everolimus for NF2 patients with progressive vestibular schwannoma reported no patients with tumor shrinkage or improvement in hearing.(13) Additional data on the effect of mTOR inhibition will become available when the results for two ongoing studies of the mTOR inhibitor rapamycin (NCT01490476 and NCT01345136) are published. In the present issue of Neuro-Oncology, Dr. Giovannini and colleagues report the effect of rapamycin on Nf2-deficient schwannoma cell lines in vitro and in vivo. Rapamycin is an inhibitor of mTORC1 and is approved by the FDA for treatment of subependymal giant-cell astrocytoma in tuberous sclerosis patients.(14) In their study, rapamycin exhibited a cytostatic, rather than cytotoxic, effect on schwannoma cell lines at nanomolar concentrations. This effect was mediated by growth arrest rather than by induction of apoptosis. Two allograft mouse models and one transgenic model model were used for in vivo drug studies. In all three models, rapamycin significantly decreased the growth of Nf2-deficient tumors by suppressing mitotic activity without affecting apoptosis. Continuous treatment by rapamycin was necessary to maintain a tumor response, as withdrawal of rapamycin led to clinical rebound with rapid tumor growth. When treatment was continued long-term (simulating treatment of human NF2 patients), rapamycin delayed tumor growth by 7 months over the 12-month treatment period. Overall, the data presented in the study provide further evidence that rapamycin can increase the time-to-progression of schwannomas in mouse models of NF2. The authors suggest that a chemoprevential trial of rapamycin should be conducted to prevent schwannoma growth in NF2 patients. To date, all clinical trials for NF2 have been designed to observe response (either tumor shrinkage or hearing improvement). However, drugs that prevent tumor growth are highly desirable since many NF2-related tumors are identified before they become symptomatic. Implementing a chemoprevention trial is now feasible through the Neurofibromatosis Clinical Trials Consortium (NFCTC), a collection of 17 clinical sites funded by the Department of Defense to conduct clinical trials to improve the quality of life of persons with neurofibromatosis (http://www.uab.edu/nfconsortium/). The study by Giovannini and colleagues raises important concerns that must be addressed in a chemoprevention trial for human NF2 patients. One potential concern is the paradoxical activation of the PI3K/AKT/mTOR pathway with mTORC1 inhibition.(15) As expected in the Nf2-deficient cell lines, rapamycin treatment significantly inhibited the phosphorylation of downstream members of the mTOR pathway, S6 and 4E-BP1. Similarly, rapamycin inhibited phosphorylation of S6 and 4E-BP1 in vivo, but in this setting was associated with upregulation of AKT1. As the authors comment, this finding raises safety concerns about treatment of NF2-related tumors with rapamycin. Most patients with NF2 have multiple tumors, and cases of malignant transformation after radiation have been reported. The effect of rapamycin on non-target tumors in patients should be monitored, as demontrated by the case report in the study. This patient was successfully treated with rapamycin for a progressive vestibular schwannoma for 4.5 years but required surgery for a growing atypical meningioma. Furthermore, the authors note that 3/9 mice treated with rapamycin versus 0/7 mice treated with saline developed uterine tumors. Rapamycin was well tolerated in mice and has a proven safety record in humans. By design, chemoprevention studies in NF2 patients will involve long-term treatment. Intense management of side effects that significantly impair quality of life (eg, rash, diarrhea, mouth sores) will be important to the success of these studies. Finally, both patients and clinicians involved in a chemoprevention trial will be concerned about rebound growth when the drug is discontinued. Alternative plans for treatment should be in place for patients whose tumors grow rapidly after drug discontinuation in order to avoid severe complications related to tumor growth. Conflict of interest statement. None declared.