83 Medical Therapy for Neurofibromatosis Type 2 Focusing on Vestibular Schwannoma

83.1 Introduction

The hallmark of neurofibromatosis type 2 (NF2) is the development of bilateral vestibular schwannomas (VSs).s. Literatur While histologically benign, VSs are a source of significant morbidity in NF2 patients, given their bilateral presentation, earlier age of onset, proximity to other critical neurovascular structures, and greater tendency to recur after treatment.s. Literatur ^, s. Literatur The coexistence of lower cranial nerve schwannomas, meningiomas, and spinal cord ependymomas further complicate clinical decision making.s. Literatur The conventional treatment options for VS include surgical excision, stereotactic radiation, and observation. Currently, there is no approved medical therapy for VS in the United States. Due to the potential high morbidity of treating VS, particularly in the NF2 population, developing novel medical therapies as an alternative has become a high priority. Fortunately, in recent years, there have been breakthroughs in the understanding of NF2 tumor biology which has led to the discovery of several important surface receptors and intracellular signaling pathways that are responsible for the growth and survival of NF2-related tumors (reviewed further in Chapter 5).s. Literatur As a result, rationally designed drugs targeting various components of this molecular pathway have been developed and tested in preclinical and clinical trials (Fig. 83‑1 , Fig. 83‑2 ).s. Literatur In this chapter, we will review current candidate drugs for the treatment of VS in the NF2 patient.

**Fig. 83.1** Overview of molecular-targeted drug therapies.

**Fig. 83.2** Targets of therapeutic drugs for vestibular schwannoma. Current strategies target the abnormal merlin-controlled growth regulator pathways through blockade of surface receptors or intracellular signaling pathways, and/or target the tumors microenvironment (endothelial cells) by inhibiting neoangiogenesis. Receptor tyrosine kinases (VEGFR, PDGFR, EGFR, and ErbB2/3) are overly expressed in *NF2*-deficinet cells leading to tumorigenesis. Inhibiting their ligands (e.g., VEGF, EGF, PGE2) or the receptors themselves have been shown to suppress downstream signaling, thereby preventing tumor growth. Multiple proneoplastic pathways are activated in merlin-deficient cells and significant “cross-talk” exists, leading to treatment failure or development of drug resistance. Small-molecule inhibitors (those ending in “-inib”) are novel in that they are able to cross the cell membrane to affect the intracellular domain of cell-surface receptors and also block the activation of various downstream signaling pathways intracellularly; while this potentially increases their breadth of inhibition, it may also lead to more “off-target” adverse side effects. HDACIs (AR-42) have a novel mechanism by which they can indirectly dephosphorylate (deactivate) AKT through its interaction with protein phosphatase 1 (PP1).

83.2 Design of Medical Therapy Trials for Vestibular Schwannoma

The ideal drug for NF2 patients would be one that (1) permanently shrinks or eradicates the tumor as opposed to simply halting its growth temporarily; (2) will allow the patient to halt loss or potentially reverse sensorineural hearing loss from tumor involvement; (3) is effective for treating both VS and meningiomas, since these frequently co-exist; (4) is safe in both adults and children, particularly since many NF2 patients are diagnosed during adolescence; and (5) has minimal side effects and is easily administered.

To date, several preclinical and clinical studies have made progress toward these goals. These studies have focused on NF2 patients with progressive or symptomatic VS; however, testing in sporadic VS has also showed efficacy, likely because both forms of VS share similar pathobiology of merlin deficiency. In fact, approximately 90% of sporadic VSs have somatic NF2 mutations. Currently, the major benchmarks to evaluate drug efficacy include (1) hearing outcomes as measured by speech discrimination (word recognition) scores and (2) radiographic outcomes based on changes in tumor volume.s. Literatur While the ideal drug would permanently eradicate the tumor, quality of life may be improved by preserving hearing or avoiding surgery, even if only temporarily. Therefore, other clinically meaningful endpoints in the NF2 population have recently gained more attention, including “progression-free survival” and “time to disease progression,” as delaying disease progression would be highly desirable in the NF2 population.s. Literatur

83.3 Targeting Angiogenesis

Vascular endothelial growth factor (VEGF) has been demonstrated to be overexpressed in both VS and surrounding endothelial cells.s. Literatur Therefore, targeting the tumor’s blood supply with angiogenesis inhibitors presents one therapeutic approach in the medical treatment of VS.

83.3.1 Bevacizumab

Bevacizumab (Avastin, Roche), a humanized anti-VEGF-A monoclonal antibody that is FDA approved for use in various cancers, was one of the first medical therapies used for treatment of NF2-associated VS (Table 83‑1 ). In retrospective studies, bevacizumab has resulted in improved hearing and radiographic tumor shrinkage in about 50% of patients with progressive VS (defined as improvement in word recognition score above the 95% critical difference and ≥20% volume reduction).s. Literatur ^, s. Literatur ^, s. Literatur A recent multicenter, phase 2 clinical trial (NCT01207687) of 14 patients with NF2 found a confirmed hearing response in 36% of patients (which was sustained ≥3 months) and radiographic response in 43% of patients, thereby confirming the efficacy and safety of bevacizumab in this subset of people with NF2 and progressive, symptomatic VSs.s. Literatur

Table 83.1 Molecular-targeted drug therapy candidates for NF2-related VS
Drug	Target	Outcomes^a	Status (ClinicalTrials.gov identifier)
Candidate drugs with clinical outcomes
Bevacizumab	VEGF mAB	57% hearing improved, 53% tumor shrinkage (retrospective).s. Literatur 36% confirmed hearing response, 57% any hearing improvement, 43% tumor shrinkage (phase 2 trial)s. Literatur	Phase 2 trials completed (NCT01207687) and ongoing (NCT01767792)
Lapatinib	EGFR and ErbB2	30.8% hearing improved, 23.5% tumor shrinkages. Literatur; (+) preclinical efficacys. Literatur	Phase 2 trial completed (NCT00973739) Phase 0 trial ongoing (NCT00863122)
Erlotinib	EGFR	No volumetric or audiological responses. Literatur; (+) preclinical efficacys. Literatur	No active clinical trials
Everolimus	mTORC1	No volumetric or audiological responses. Literatur but study limited by small number of patients, many of who had failed previous medical therapy; (+) preclinical efficacys. Literatur	Phase 2 trials completed (NCT01490476, NCT01419639) and ongoing (NCT01345136) Phase 0 trial ongoing (NCT01880749)
Aspirin	COX enzyme; IkB kinase	A significant inverse association was found among aspirin users and spontaneous VS growth (OR: 0.50)s. Literatur	No active clinical trials
Candidate drugs showing preclinical efficacy
Nilotinib	PDGFR, c-KIT, bcr-abl	(+) preclinical efficacys. Literatur ^, s. Literatur	Phase 2 trial ongoing (NCT01201538)
AR-42	HDACI	(+) preclinical efficacys. Literatur ^, s. Literatur	Phase 0 trial ongoing (NCT02282917)
AR-12	PDK-1	(+) preclinical efficacys. Literatur	No active clinical trials
Sorafenib	PDGFR, c-Raf, VEGFR-2, -3	(+) preclinical efficacys. Literatur	No active clinical trials
Selumetinib	MEK1/2	(+) preclinical efficacys. Literatur ^, s. Literatur	No active clinical trials
Other novel candidate drugs
Axitinib	VEGFR-1/2/3	No preclinical studies in VS	Phase 2 trial ongoing (NCT02129647)
Endostatin	VEGF, TNF-α	No preclinical studies in VS	Phase 2 trial ongoing (NCT02104323)
PTC299	VEGF mRNA	No preclinical studies in VS	Phase 2 trial ongoing (NCT00911248)
^a Direct comparisons of outcomes between studies are limited by the variable definitions used for hearing improvement and volumetric tumor response between studies.

It is hypothesized that bevacizumab’s effects on reducing tumor volume is secondary to decreasing vascular permeability and decreasing outgrowth of new vessels, as opposed to having a direct antiproliferative effect.s. Literatur Unfortunately, tumor regrowth has been noted upon discontinuation of the drug, which may occur shortly after 6 months or longer following discontinuation of the drug; as a result, prolonged treatment may be necessary in order to sustain clinical benefit.s. Literatur This can be challenging clinically given the relatively high incidence of long-term toxicities of bevacizumab, namely hypertension (58%) and proteinuria (62%).s. Literatur In addition, bevacizumab impairs wound healing.s. Literatur This is of particular concern for NF2 patient who are often afflicted with other tumors concurrently, which may require surgery.s. Literatur Another ongoing clinical trial (NCT01767792) studying bevacizumab for children and young adults with hearing loss resulting from an NF2-associated VS will further investigate and expand upon the findings from this study.

83.3.2 Potential Future Therapies Targeting Angiogenesis

Given the initial success of previous studies with bevacizumab in NF2 patients, other methods of targeting VEGF have been explored. Recombinant human endostatin, formed by proteolytic cleavage of collagen XVIII, may impede the formation of blood vessels by inhibiting the migration of vascular endothelial cells through its interaction in multiple intracellular pathways.s. Literatur A phase 2 clinical trial (NCT02104323) is ongoing in Beijing Tiantan Hospital using endostatin in patients with NF2-related tumors. Axitinib (Inlyta, Pfizer), a selective tyrosine kinases inhibitor (TKI) that is primarily active against VEGF receptors-1, -2, -3, is another promising antiangiogenic small molecule currently being tested in a phase 2 clinical trial for NF2 patients with progressive VS (NCT02129647).s. Literatur Lastly, PTC299 (PTC Therapeutics; South Plainfield, NJ) is a small molecule that inhibits VEGF at the posttranscriptional level, binding to the 5′- and 3′-untranslated regions of VEGF mRNA, thereby limiting its production.s. Literatur A clinical trial was previously underway but is currently suspended according to clinicaltrials.gov.

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83 Medical Therapy for Neurofibromatosis Type 2 Focusing on Vestibular Schwannoma