Methods of treatment and diagnosis of multiple myeloma progression

Patent metadata

Field	Value
Publication number	US-2023340604-A1
Application number	US-202217659946-A
Country	US
Kind code	A1
Filing date	Apr 20, 2022
Priority date	Apr 20, 2022
Publication date	Oct 26, 2023
Grant date	—

Abstract

A method of treating multiple myeloma, comprising administering one or more agents increasing or inhibiting the expression or activity of one or more MM biomarkers to inhibit the progression of multiple myeloma, wherein the one or more MINI biomarkers correspond to gene products from one or more of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK1, CCND2, NES, PKP2, C1orf226, IFITM1, CDH23, AGRN, DHX58, and LINC02576. A method of diagnosing and treating multiple myeloma in a subject comprises, (a) measuring the level of one or more biomarkers in a sample; (b) comparing the level of the one or more biomarkers to a reference level of the one or more biomarkers; (c) making a diagnosis based on the result of the comparing step; and (d) treating the subject with one or more active agents where the subject is diagnosed with multiple myeloma.

First claim

1 . A method of diagnosing and treating multiple myeloma (MM) in a subject comprising,
(a) measuring a level of one or more biomarkers in a sample from the subject; (b) comparing the level of the one or more biomarkers to a reference level of the one or more biomarkers; (c) making a diagnosis based on the result of the comparing step, and (d) treating the subject with one or more active agents where the subject is diagnosed with multiple myeloma, wherein said biomarker(s) is selected from a group consisting of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK1, CCND2, NES, PKP2, C1 and 1226.

2 . The method of claim 1 , comprising measuring the levels of at least 5 MM biomarkers.

3 . The method of claim 1 , comprising measuring the levels of at least 5 MM biomarker s, wherein the biomarker(s) is selected from one or more of IFITM1, CDH23, AGRN, DHX58, and LINC02576.

4 . The method of claim 1 , wherein the biomarker is GABRA3.

5 . The method of claim 1 , wherein the sample comprises a, blood plasma cell or bone marrow cells.

6 . The method of claim 1 , wherein the sample is a urine sample.

7 . The method of claim 4 , comprising administering a GABAA or GABRA3 receptor antagonist.

8 . The method of claim 7 , wherein the antagonist is one or more selected from the group consisting of flumazenil, thiocolchicoside, pentetrazol, picrotoxin, topiramate, loreclezole, etomitade and propofol.

9 . The method of claim 7 , wherein the antagonist is an antibody directed against the GABAA alpha-3 subunit.

10 . The method of claim 7 , wherein the antagonist is a polynucleotide.

11 . The method of claim 10 , wherein the polynucleotide is an RNA selected from the group consisting of a short interfering RNA (siRNA), a short hairpin RNA (shRNA) molecule, an antisense RNA, and a microRNA (miRNA).

12 . The method of claim 10 , wherein the polynucleotide is an A-to-1 RNA edited GABRA3 encoded polynucleotide.

13 . A method for determining MM disease progression or risk for metastasis in a subject with multiple myeloma, comprising the steps of:
(a) measuring the level of one or more biomarkers in a first sample obtained from the subject with multiple myeloma at a first time point; (b) measuring the level of the one or more biomarkers in a second sample obtained from the subject at a second time point; (c) comparing the level of the one or more biomarkers at the first time point to the level of the one or more biomarkers at the second time point; (d) determining the disease progression be on the result of step (c); and (e) further treating the subject with one or more active agents if the multiple myeloma has Progressed
wherein said biomarker(s) is selected fro a group consisting of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK.1, CCND2, NES, PKP2, C 1 and f226.

14 . A method for determining the efficacy of a treatment for multiple myeloma in a subject, comprising the steps of:
(a) measuring the level of one or more biomarkers in a first sample obtained from the subject at a first time point; (b) measuring the level of the one or more biomarkers in a second sample obtained from the subject at a second time point, wherein the subject is under treatment at the second time point; (c) comparing the level of the one or more biomarkers at the first time paint to the level of the one or more biomarkers at the second time point; (d) determining the efficacy of the treatment based on the result of step (c); and (e) further treating the subject with one or more active agents if the efficacy has been found to be insufficient for treatment. In certain preferred embodiments, the one or more active agents in step (e) include one or more active agents that were not administered in the previous treatment, wherein said biomarker(s) is selected from a group consisting of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK.1, CCND2, NES, PKP2, C 1 and f226.

15 . The method of diagnosing and treating of claim 1 , wherein the treatment comprising administering to a subject in need thereof, one or more agents increasing or inhibiting the expression or activity of one or more MM biomarkers in amounts sufficient to inhibit the progression of multiple myeloma in the subject,
wherein the one or more MM biomarkers correspond to gene product(s) is selected from the group consisting of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK.1, CCND2, NES, PKP2 and C1orf226.

16 . The method of claim 15 , wherein the one or more agents inhibit the expression or activity of biomarker identified from one or more of GABRA3, CTAG2, MAGEA6, SOHLH1, MAGEA1, AFAP1-AS1; CBX2, LINC00484, KIF7, TMSB15A, NEK2, NTRK.1, CCND2, NES, PKP2, and C1orf226.

17 . The method of claim 15 , wherein the one or more agents increase the expression or activity of biomarker selected from one or more of IFITM1, CDH23, AGRN, DHX58, and LINC02576.

18 . The method of claim 16 , wherein the one or more agents comprise a small molecule GABAA or GABRA3 receptor antagonist selected from the group consisting of flumazenil, thiocolchicoside, pentetrazol, picrotoxin, topiramate, loreclezole, etomitade and propofol.

19 . The method of claim 16 , wherein the one or more agents comprise an antibody directed against the GABAA alpha-3 subunit.

20 . The method of claim 13 , wherein the one or more agents comprise an RNA selected from the group consisting of short interfering RNA (siRNA), short hairpin RNA (shRNA) molecule, antisense RNA, and microRNA (miRNA).

Assignees

• Morehouse School Of Medicine

Inventors

• Lillard Jr James W
• Adebayo Olayinka

Classifications

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title