# US 10,610,563 B2 · Use of ubiquitin-proteasome system inhibitors for treatment of tumors associated with neurofibromatosis type-2 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,610,563 B2 - Document ID: US10610563B2 - Status: Granted - Kind: B2 - Application number: 15/529,730 - Filed: 2015-11-24 - Published: 2017-12-21 - Granted: 2020-04-07 - Earliest claimed: 2014-11-25 - Assignees: Bioxcel Corporation - Applicants: Bioxcel Corporation - Inventors: Krishnan Nandabalan; Sameer Sharma; Luca Rastelli - Web page: https://patentgrep.com/patent/US10610563B2 ## CPC - A61K 38/05: Dipeptides - A61K 31/39: having oxygen in the same ring - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 31/69: Boron compounds - A61K 38/07: Tetrapeptides - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - G01N 33/5752: of the lungs - G01N 33/57557: {of other specific parts of the body, e.g. brain} - G01N 2333/82: Translation products from oncogenes - G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## 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. ## Claims ### Claim 1 A method of treating, preventing or ameliorating a tumor or a symptom arising due to a neurofibromatosis type-2 gene mutation in a subject comprising administering to said subject a therapeutically effective amount of bortezomib. ### Claim 2 (depends on 1) The method as claimed in claim 1, wherein said tumor is a neurofibromatosis type-2/merlin deficient tumor. ### Claim 3 (depends on 2) The method as claimed in claim 2, wherein the neurofibromatosis type-2 deficient tumor is selected from the group consisting of vestibular schwannomas, unilateral schwannomas, bilateral vestibular schwannomas, spinal cord schwannomas, sporadic schwannomas, peripheral nerve schwannomas, meningioma, mesothelioma, ependymoma, glioma, astrocytoma, and combinations thereof. ### Claim 4 (depends on 1) The method as claimed in claim 1, further comprising administering a second ubiquitin-proteasome system inhibitor selected from the group consisting of PI-083, MLN 9708, MLN 4924, MLN 519, Carfilzomib, ONX 0912, CEP-1877, NPI-0052, BU-32 (NSC D750499-S), PR-171, IPSI-001, and a natural product with proteasome-inhibitory effects. ### Claim 5 (depends on 4) The method as claimed in claim 4, wherein the proteasome inhibitor is carfilzomib. ### Claim 6 (depends on 1) The method as claimed in claim 1, wherein the bortezomib is a pharmaceutically acceptable salt, derivative, polymorph, racemate, stereoisomer, conjugate or complex thereof. ### Claim 7 (depends on 1) The method as claimed in claim 1, wherein the bortezomib is administered at a dose in a range of about 0.5 mg/m2 to about 100 mg/m2. ### Claim 8 (depends on 1) The method as claimed in claim 1, wherein the bortezomib is administered in a dose range of about 0.1 mg to about 50 mg per day. ### Claim 9 (depends on 1) The method as claimed in claim 1, wherein the bortezomib is administered via a delivery route selected from the group consisting of parenteral, intra-tumoral, oral, intravenous, transdermal, subcutaneous and intramuscular. ### Claim 10 (depends on 1) The method as claimed in claim 1, wherein the method further comprises administering to said subject one or more additional tumor treatments. ### Claim 11 (depends on 10) The method as claimed in claim 10, wherein the one or more additional treatments are selected from the group consisting of chemotherapeutic agents, radiotherapeutic agents, antibody-based therapeutic agents, steroids, and combinations thereof. ### Claim 12 A method of enhancing LATS activity in a tumor having compromised activity of neurofibromatosis type-2/merlin comprising administering bortezomib to a subject having the tumor. ### Claim 13 (depends on 12) The method as claimed in claim 12, wherein the tumor is from a schwannoma selected from the group consisting of: a vestibular schwannoma, a unilateral schwannoma, a bilateral vestibular schwannoma, a spinal cord schwannoma, a sporadic schwannoma, and a peripheral nerve schwannoma. ### Claim 14 (depends on 12) The method as claimed in claim 12, wherein the bortezomib is administered in an amount sufficient to increase LATS activity by at least 20%, at least 30%, at least 50%, at least 60%, at least 80%, at least 100%, or at least 150% compared to the activity in an untreated cell having compromised activity of neurofibromatosis type-2/merlin. ### Claim 15 (depends on 4) The method of claim 4, wherein the second ubiquitin-proteasome system inhibitor is a natural product with proteasome-inhibitory effects and said natural product is selected from the group consisting of green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG), curcumin, and soy isoflavone genistein. ### Claim 16 (depends on 7) The method of claim 7, wherein the bortezomib is administered to patients in a dose range of about 0.5 mg/m2 to about 1.3 mg/m2. ### Claim 17 (depends on 8) The method of claim 8, wherein the bortezomib is administered to patients in a dose range of about 1 mg to about 10 mg per day. ### Claim 18 (depends on 9) The method of claim 9, wherein the administration is subcutaneous or intratumoral. ### Claim 19 (depends on 18) The method of claim 18, wherein the administration is subcutaneous. ### Claim 20 (depends on 10) The method of claim 10 wherein the additional treatment is a conventional chemotherapeutic agent. ### Claim 21 (depends on 20) The method of claim 20, wherein the chemotherapeutic agent is selected from the group consisting of alkylating agents, anti-metabolites, plant alkaloids, plant terpenoids, topoisomerase inhibitors, antineoplastics, and combinations thereof. ### Claim 22 (depends on 10) The method of claim 10 wherein the additional treatment is an antibody-based therapeutic agent. ### Claim 23 (depends on 22) The method of claim 22, wherein the antibody-based therapeutic agent is selected from the group consisting of gemtuzumab, alemtuzumab, rituximab, trastuzumab, nimotuzumab, cetuximab, and bevacizumab. ### Claim 24 (depends on 10) The method of claim 10 wherein the additional treatment is a steroid. ### Claim 25 (depends on 24) The method of claim 24, wherein the steroid is dexamethasone.