Proteasome Inhibitors Have Therapeutic Potential for Tumors Associated with Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2) is an inherited genetic disorder caused by inactivation of the NF2 tumor suppressor gene. It is often associated with central and peripheral nervous system tumors, notably schwannomas and meningiomas. Although these tumors are usually histologically benign, they are often progressive, highly morbid, and resistant to surgery, radiation, and standard chemotherapies.

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As part of large-scale drug screening studies in preclinical models of NF2, Massachusetts General Hospital researchers recently identified brigatinib, an FDA-approved multi–tyrosine kinase inhibitor, as a potent therapy for NF2-related malignancies in preclinical models. That drug is now in an NF2 clinical trial.

Subsequently, the researchers used the earlier data to identify other drugs that might have cytotoxic effects in NF2-deficient meningioma and schwannoma cell models. They pinpointed a subset of drugs targeting the ubiquitin proteasome pathway (UPP) as potential candidates. The UPP, a network of enzymes and the multi-subunit 26S proteasome helps sustain the intricate balance between cell survival and apoptosis.

Srirupa Bhattacharyya, PhD, a research fellow at Mass General in the Department of Neurology and Center for Genomic Medicine, Vijaya Ramesh, PhD, co-director of Mass General Neuroscience and associate neurologist at Mass General, and colleagues report the findings in Neuro-Oncology.

Methods

The team tested three drugs targeting the UPP that have demonstrated strong antitumor activity:

• Ixazomib, FDA-approved for the treatment of multiple myeloma and being extensively studied for other hematological malignancies
• Pevonedistat, which has FDA breakthrough therapy status for the treatment of higher-risk myelodysplastic syndromes
• TAK-243 (also known as MLN7243), also an investigational drug

Principal Results

The key observations were that:

• Ixazomib and TAK-243 significantly inhibited proliferation in human meningioma and Schwann cell models and induced apoptosis in all meningioma lines tested
• Global transcriptomic analysis demonstrated that in meningioma lines, both drugs significantly downregulated the expression of the proto-oncogenes KIT, PDGFRA, and SKP2
• Several genes involved in endoplasmic reticulum stress and activation of the unfolded protein response pathway were upregulated, which may be partially responsible for the observed cell death
• In mice bearing malignant grade III meningioma xenografts, ixazomib, and TAK-243 significantly suppressed tumor growth, with ixazomib being more effective
• Ixazomib was also effective in an allograft model of mouse schwannoma and a xenograft model of patient-derived schwannoma without any significant adverse effects

Therapeutic Implications

The efficacy of proteasome inhibitors in meningioma and schwannoma models lays the groundwork for clinical trials of these drugs in patients with NF2. Many altered pathways downstream of NF2 loss could be shared among other meningiomas, suggesting the drugs might be effective in all meningiomas regardless of NF2 status.

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