JPWO2020219668A5 - - Google Patents

Claims (16)

A pharmaceutical composition comprising a TXNRD1 inhibitor for treating a RAS mutant cancer in a subject, wherein said TXNRD1 inhibitor is auranofin , piperlongumine, D9, TRi-1, TRi-2, myricetin, PMX464, The pharmaceutical composition selected from the group consisting of PX12, brevetoxin-2, manumycin A, etaselen, aurothioglucose, protoporphyrin IX, and anti-TXNRD1 antibody. A pharmaceutical composition comprising an inhibitory nucleic acid that inhibits TXNRD1 expression for treating RAS mutant cancer in a subject . SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and 3. The pharmaceutical composition of claim 2, comprising a sequence selected from the group consisting of SEQ ID NO: 12 or any complement thereof. the subject exhibits elevated levels of RAS protein expression in cancer cells prior to treatment;
or,
The subject has pain in the upper abdomen radiating to the back, anorexia or unintentional weight loss, depression, onset diabetes, blood clots, fatigue, yellowing of the skin and whites of the eyes (jaundice), bloating, nausea, and vomiting. exhibiting one or more signs or symptoms selected from
or,
Subject is TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A, SF3B1, EPC1, ARID2, ATM, ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6, ROBO2, KDM6A, PREX2, ERBB2, MET, FGFR1, CDK6, PIK3R3, PIK 3CA , containing one or more point mutations in BRCA1, BRCA2, or PALB2;
or,
the subject is a human
The pharmaceutical composition according to any one of claims 1-3. 5. Any one of claims 1-4, wherein the RAS mutant cancer is lung cancer, mucinous adenoma, pancreatic cancer, colorectal cancer, skin cancer, endometrial cancer, testicular germ cell carcinoma, or adrenal cancer. pharmaceutical composition of KRAS wherein the RAS mutant cancer is selected from the group consisting of G12C, G12D, G12V, G12A, G12S, G12R, G13D, G13C, G13S, G13R, G13A, G13V, Q61H, Q61L, Q61R, Q61K, Q61P, and Q61E 6. The pharmaceutical composition of claim 5, comprising a , NRAS, or HRAS mutation. Administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, iontophoretically, transmucosally, or intramuscularly The pharmaceutical composition according to any one of claims 1 to 6 , which is formulated for 8. The pharmaceutical composition of any one of claims 1-7, wherein the subject is administered one or more additional therapeutic agents separately, sequentially, or concurrently . composition . 9. The pharmaceutical composition of Claim 8 , wherein the additional therapeutic agent is selected from the group consisting of paclitaxel, gemcitabine, AMG 510, 5-FU (fluorouracil), and irinotecan. A pharmaceutical composition according to any one of claims 1 to 9 , administered daily for 6 weeks , 12 weeks or more . A pharmaceutical composition comprising a TXNRD1 inhibitor for use in a method of monitoring therapeutic efficacy of a TXNRD1 inhibitor in a subject diagnosed with a RAS mutant cancer, said method comprising:
(a) detecting TXNRD1 protein level in a test sample obtained from said subject after said subject has been administered said TXNRD1 inhibitor; and (b) TXNRD1 protein level in said test sample is determining that said TXNRD1 inhibitor is effective if it is reduced compared to levels observed in a control sample obtained from said subject prior to administration;
The pharmaceutical composition comprising: the TXNRD1 inhibitor is auranofin, piperlongumine, D9, TRi-1, TRi-2, myricetin, PMX464, PX12, brevetoxin-2, manumycin A, etaselen, aurothioglucose, protoporphyrin IX, anti-TXNRD1 antibody, or 12. The pharmaceutical composition according to claim 11 , which is an inhibitory nucleic acid that inhibits TXNRD1 expression. The inhibitory nucleic acid is shRNA, antisense oligonucleotide, or sgRNA, optionally said inhibitory nucleic acid is SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 , SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12 , or any complement thereof. pharmaceutical composition . A pharmaceutical composition comprising at least one TXNRD1 inhibitor for use in a method of inhibiting RAS mutant cell proliferation in a subject, said method comprising administering said pharmaceutical composition to said subject, said at least one TXNRD1 inhibitor is auranofin, piperlongumine, D9, TRi-1, TRi-2, myricetin, PMX464, PX12, brevetoxin-2, manumycin A, etaselen, aurothioglucose, protoporphyrin IX, anti-TXNRD1 an antibody, and an inhibitory nucleic acid that inhibits TXNRD1 expression, said subject suffering from a disease or condition characterized by increased expression levels and/or increased activity of RAS and/or TXNRD1; Optionally, the inhibitory nucleic acid is SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, No. 11, and SEQ ID No. 12, or any complement thereof,
Said pharmaceutical composition . 15. The pharmaceutical composition of any one of claims 1-14 , wherein the method further comprises administering a therapeutically effective amount of gemcitabine to the subject . 16. The pharmaceutical composition of any one of claims 1-15 , wherein the method further comprises administering to the subject a therapeutically effective amount of a KRAS ^G12C inhibitor, wherein said KRAS ^G12C inhibitor may be AMG 510. things .