Methods of treating cancer by targeting cold tumors

Patent metadata

Field	Value
Publication number	US-12357633-B2
Application number	US-202017618415-A
Country	US
Kind code	B2
Filing date	Jun 12, 2020
Priority date	Jun 13, 2019
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

Methods are provided for the treatment of cancer or neoplastic diseases and the like, by administering 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-4-yl]-2-fluoro- benzonitrile (compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising compounds useful for the inhibition of lysine specific demethylase-1 (LSD-1) to patients in need thereof. Methods are further drawn to administering compositions described herein to patients having neoplastic cells that express RCOR2.

First claim

What is claimed is:

1. A method of treating cancer in a subject in need thereof, the method comprising:
(a) identifying a patient having a cancer tumor that is a diagnostic positive cold tumor; and
(b) administering to the patient a composition comprising a therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein the diagnostic positive cold tumor exhibits a cold tumor signature as defined by
(a) low or no CD8 T cell infiltration within the tumor; and/or
(b) exhibition of T cell non-inflamed or T cell excluded based on the presence of T cells within the tumor; and/or
(c) the presence of T cells within the tumor is measured or estimated by gene expression levels of T cell markers in bulk RNA profiling data, and

wherein the patient's cancer cells exhibit a decrease in the gene expression of one or more interferon response genes, wherein the decrease in the gene expression is relative to the gene expression of a control gene.

2. The method of claim 1 , wherein the patient:
(a) has failed single checkpoint inhibitor (CPI) therapy, has minimal response to CPI therapy, or no therapeutic effect is observed for CPI therapy; and
(b) cells of the tumor display a high gene expression of REST Corepressor 2 (RCOR2) relative to the median RCOR2 gene expression of tumors in other patients having the same tumor type.

3. The method of claim 1 , wherein the patient:
(a) is naïve to a CPI therapy; and
(b) cells of the tumor display a high gene expression of RCOR2 relative to the median RCOR2 gene expression of tumors in other patients having the same tumor type.

4. The method of claim 2 , wherein:
(a) high gene expression of RCOR2 is in the top 25% of expression of tumors in other patients having the same tumor type; or
(b) high gene expression of RCOR2 is in the top 10% of expression of tumors in other patients having the same tumor type.

5. The method of claim 2 , wherein:
(a) the CPI therapy comprises anti-programmed cell death protein 1 (PD1) and/or programmed death-ligand 1 (PD-L1) therapy; and
(b) the patient's cancer cells display a high gene expression of REST Corepressor 2 RCOR2).

6. The method of claim 1 , wherein:
the patient's cancer cells display a high gene expression of RCOR2.

7. The method of claim 1 , wherein:
(a) the patient's cancer cells exhibit an increase in the gene expression of one or more of the following genes: AK056486, NKAIN1, FAM183A, SAMD13, LINC00622, CHRNB2, MEX3A, IGSF9, C1ORF192, CCDC181, OCLM, PPFIA4, PANK1, B4GALNT4, GAS2, MS4A8, MYRF, RCOR2, FLRT1, AK313893, NXPH4, BC073932, MSI1, CCDC169, FREM2, ATP7B, AF339817, AK124233, GPX2, PAR5, PLA2G4F, IGDCC3, GOLGA6L10, UBE2Q2P2, WDR93, PDIA2, CASKIN1, AK096982, TOX3, AK057689, C16ORF3, AK127378, EFNB3, DNAH2, ANKRD13B, SOCS7, RAMP2-AS1, FAM171A2, ADAM11, METAZOA_SRP_75, CBX2, ZNF850, LOC100379224, TTYH1, VN1R1, MEIS1-AS3, LONRF2, BC022892, KLHL23, AX747067, CCDC108, IRS1, KIF1A, FLRT3, SIM2, IGSF5, CECR5-AS1, FAM227A, AX747137, FGD5P1, ACVR2B, LOC646903, FGFR3, FLJ13197, SLC10A4, TTC23L, MCIDAS, GUSBP9, GPR98, SEMA6A, PCDHGC4, USP49, TMEM151B, AK125212, PACRG, AK123300, COL28A1, SOSTDC1, AK098769, FKBP6, DPY19L2P4, EPO, CTTNBP2, KIAA1549, TAS2R5, FAM86B2, DQ595103, CHD7, AK094577, WNK2, TMEFF1, AL390170, MUM1L1, HS6ST2, and PNCK; and
(b) the increase in the gene expression is relative to the gene expression of a control gene.

8. The method of claim 7 , wherein the patient's cancer cells:
(a) exhibit an increase in the gene expression of at least about 10% or at least about 15% of the genes where expression levels are measured; or
(b) exhibit an increase in the gene expression of at least about 20%, at least about 25%, at least about 30%, or at least about 35% of the genes where expression levels are measured; or
(c) exhibit an increase in the gene expression of at least about 40%, at least about 45%, at least about 50%, or at least about 55% of the genes where expression levels are measured; or
(d) exhibit an increase in the gene expression of at least about 60%, at least about 65%, at least about 70%, or at least about 75% of the genes where expression levels are measured; or
(e) exhibit an increase in the gene expression of at least about 80% of the genes where expression levels are measured.

9. The method of claim 1 , wherein:
the patient's cancer cells exhibit a decrease in the gene expression of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% of the interferon response genes where expression levels are measured, and wherein the decrease in the gene expression is relative to the gene expression of a control gene.

10. The method of claim 1 , wherein the interferon response genes are selected from: AC124319.1, ADAR, APOL6, ARID5B, ARL4A, AUTS2, B2M, BANK1, BATF2, BPGM, BST2, BTG1, CIR, CIS, CASP1, CASP3, CASP4, CASP7, CASP8, CCL2, CCL5, CCL7, CD274, CD38, CD40, CD69, CD74, CD86, CDKNIA, CFB, CFH, CIITA, CMKLR1, CMPK2, CMTR1, CSF2RB, CXCL10, CXCL11, CXCL9, DDX58, DDX60, DHX58, EIF2AK2, EIF4E3, EPSTI1, FAS, FCGRIA, FGL2, FPR1, GBP4, GBP6, GCH1, GPR18, GZMA, HELZ2, HERC6, HIFIA, HLA-A, HLA-B, HLA-DMA, HLA-DQA1, HLA-DRB1, HLA-G, ICAM1, IDO1, IFI27, IFI30, IFI35, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IFITM2, IFITM3, IFNAR2, IFL10RA, IL15, IL15RA, IL18BP, IL2RB, IL4R, IL6, IL7, IRF1, IRF2, IRF4, IRF5, IRF7, IRF8, IRF9, ISG15, ISG20, ISOC1, ITGB7, JAK2, KLRK1, LAP3, LATS2, LCP2, LGALS3BP, LYSE, LYSMD2, 1-MAR, METTL7B, MT2A, MEHFD2, MVP, MX1, MX2, MYD88, NAMPT, NCOA3, NFKB1, NFKBIA, NLRC5, NMI, NOD1, NUP93, OAS2, OAS3, OASL, OGFR, P2RY14, PARP12, PARP14, PDE4B, PELI 1, PFKP, PIM1, PLA2G4A, PLSCR1, PML, PNP, PNPT1, PSMA2, PSMA3, PSMB10, PSMB2, PSMB8, PSMB9, PSME1, PSME2, PTGS2, PTPN1, PTPN2, PTPN6, RAPGEF6, RBCK1, RIPK1, RIPK2, RNF31, RSAD2, RTP4, SAMD9L, SAMHD1, SECTM1, SELP, SERPING1, SLAMF7, SLC25A28, SOCS1, SOCS3, SOD2, SP110, SPPL2A, SRI, SSPN, ST3GAL5, ST8SIA4, STAT1, STAT2, STAT3, STAT4, TAP1, TAPBP, TDRD7, TNFAIP2, TNFAIP3, TNFAIP6, TNFAIP10, TORIB, TRAFD1, TRIM14, TRIM 21, TRIM25, TRIM 26, TXNIP, UBE2L6, UPP1, USP18, VAMP5, VAMP8, VCAM1, WARS, XAF1, XCL1, ZBP1, and ZNFX1.

11. The method of claim 1 , wherein:
(a) the compound of Formula (I) or a pharmaceutically acceptable salt thereof is an inhibitor of Lysine-specific histone demethylase 1 (LSD-1); and/or
(b) the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a reversible antagonist to LSD-1; and/or
(c) the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a reversible inhibitor of LSD-1.

12. The method of claim 11 , wherein:
(a) when LSD-1 is blocked, infiltration of T cells is thereby enabled, thus allowing anti-PDL1 and/or anti-PD1 therapy to retard tumor growth and/or reduce tumor size; and/or
(b) LSD-1 is inhibited from demethylating histone complexes, and thereby infiltration of T cells is enabled, thus allowing anti-PDL1 and/or anti-PD1 therapy to retard tumor growth and/or tumor size; and/or
(c) LSD-1 is prevented from forming a functional protein complex with RCOR2, and thereby infiltration of T cells is enabled, thus allowing anti-PDL1 and/or anti-PD1 therapy to retard tumor growth and/or tumor size.

13. The method of claim 1 , wherein the subject's cancer has a high non-synonymous mutational bu

Assignees

• Celgene Corp

Inventors

• Filvaroff Ellen
• Fox Brian
• Aronchik Ida
• Chow Tracy

Classifications

• C07K16/2827

  against B7 molecules, e.g. CD80, CD86 · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• A61K31/365

  Lactones · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title