Use of ubiquitin-proteasome system inhibitors for treatment of tumors associated with neurofibromatosis type-2

Inventors

Nandabalan, Krishnan • Sharma, Sameer • Rastelli, Luca

Assignees

Bioxcel LLC

Abstract

The invention discloses a method of treating, preventing or ameliorating tumor or symptoms resulting from defective neurofibromatosis type-2 gene in a subject by administering to the subject a therapeutically effective amount of a ubiquitin-proteasome system inhibitor which inhibits or slows the growth of neurofibromatosis type-2-deficient tumor or associated symptoms. The invention also includes methods of diagnosis and screening of patients for neurofibromatosis type-2 and mesothelioma.

Core Innovation

The invention is directed to methods of treating, preventing, or ameliorating a tumor or a symptom arising due to a neurofibromatosis type-2 gene mutation in a subject by administering a therapeutically effective amount of bortezomib. The disclosed scope includes tumors associated with neurofibromatosis type-2 gene defects, including NF2-deficient schwannomas and meningiomas and NF2-dependent mesothelioma.

The document provides a mechanistic rationale based on proteasome inhibition. Proteasome inhibition affects CRL4^DCAF1 and Hippo pathway signaling, including LATS1/2 and YAP/TAZ, and indicates that bortezomib can enhance LATS activity. The enhanced LATS activity is described as leading to tumor cell apoptosis.

The document further links the therapeutic strategy to patient selection concepts for NF2-altered individuals. It describes diagnostic/companion diagnostic concepts for selecting NF2-altered patients, and also references BAP1-dependent mesothelioma. In a disclosed NF2 knockout model, proteasome activity inhibition is described as dose- and time-dependent, associated with increased caspase 3/7 activity, and recovery/upregulation of LATS1 protein after bortezomib treatment.

Claims Coverage

The document contains two independent claims. Across these, the inventive features are centered on using bortezomib to treat tumors or symptoms arising from neurofibromatosis type-2 gene mutation and administering bortezomib to enhance LATS activity in tumors with compromised neurofibromatosis type-2/merlin activity.

Claim coverage focuses on administering bortezomib for NF2-mutation-associated tumor treatment, prevention, or amelioration, and separately on administering bortezomib to enhance LATS activity in tumors with compromised neurofibromatosis type-2/merlin activity. Dependent claims refine tumor subtypes, administration routes, and quantitative or dose constraints, and allow additional therapies from specified classes or a second ubiquitin-proteasome system inhibitor.

Stated Advantages

Documented Applications