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US-20260125683-A1 - TREATMENT OF CANCERS HAVING A DRUG-RESISTANT MESENCHYMAL CELL STATE

US20260125683A1US 20260125683 A1US20260125683 A1US 20260125683A1US-20260125683-A1

Abstract

The subject matter disclosed herein is generally directed to methods of treating a tumor capable of an epithelial-to-mesenchymal transition (an EMT cancer) by targeting the mesenchymal cell state. Disclosed are novel gene dependencies in the mesenchymal cell state. Also, disclosed are novel drugs that target the mesenchymal cell state.

Inventors

  • Andrew Aguirre
  • Kevin KAPNER
  • Kyle Evans

Assignees

  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260507
Application Date
20250912

Claims (20)

  1. 1 - 4 . (canceled)
  2. 5 . A method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method comprising: administering to the subject one or more agents capable of inhibiting the expression or activity of CDS2, ELMO2, ITGAV, AP1M1, FERMT2, CHMP4B, PTK2, ITGB5, PRKAR1A, ACTR1A, SRF, ZEB1, MTOR, DNM1L PSMB7, MOB4, TEAD1, DOCK5, ACTR3, BCAR1, UFM1, TIPARP, ILK, RSU1, WWTR1, NCKAP1, ATP6V1C1, MYH9, FOSL1, LIMS1, GNB1, EFR3A, ARHGEF7, WDR7, PKN2, CEMIP2, TEAD1, CTDNEP1, MARK3, VCL, CDC42, BCAR1, EGLN1, UFM1, GPX4, and/or CRK, thereby treating the subject having the EMT cancer.
  3. 6 - 35 . (canceled)
  4. 36 . The method of claim 5 , comprising administering to the subject one or more agents capable of inhibiting CDS2 expression or activity.
  5. 37 . The method of claim 5 , further comprising: identifying the cancer as an EMT cancer by detecting in the cancer the expression of one or more genes identified as positively correlated with EMT Down signatures and/or as negatively correlated with EMT Up signatures, wherein the one or more genes identified as positively correlated with EMT Down signatures are selected from among PTPN6, ILDR1, TSTD1, LCN2, MYO6, MFSD6, AMN, DDR1, PPL, C2orf15, AREG, CD9, FAM160A1, ENPP5, CD24, SMIM22, RAB25, PRRG2, CLDN4, RNF223, PLA2G4F, LLMO3, MAP7, MAL2, CBLC, KRTCAP3, MACC1, F11R, SPINT1, CNKSR1, CGN, IRF6, ESRP2, MPZL3, OVOL2, BSPRY, PRSS22, FXYD3, TJP2, PKP2, TMC5, RNF43, USP43, DLG3, PRKCZ, PKP3, ANO9, GRB7, JUP, CDH3, C11orf52, MYO5B, PATJ, TSPAN1, ZNF165, EPHA1, ELF3, BICDL22, TJP3, MUC20, MARVELD2, TC2N, CDS1, CLDN7, GRHL2, C1orf116, EPN3, PSD4, FAAH, OVOL1, SYNE4, IQANK1, MARVELD3, CRB3, KDF1, PRSS8, MAPK3, MAPK13, S100A14, ERBB3, GALNS, KRT19, EPS8L1, TMC4, ESRP1, SOWAHB, ST14, CDC42BPG, RAB17, CDH1, SH2D3A, LSR, B3GN3T, C1orf210, MPZL2, FUT3, SPINT2, C6orf132, PLEKHA7, TMC5, ICA1, TPD52L1, KLK8, SFTA2, KRT8, LAD1, IRF6, KLF5, PRR15, BICDL2, LIPH, LSR, FXYD3, EPCAM, MAL2, C2N, SPINT1, TCM5, ASS1, COBL, ACSL5, GPX2, MYZAP, KIAA1217, SCNN1A, B3GNT3, MISP, VGLL1, ITGB6, DOK7, HSH2D, SYT8, SH3YL1, SFN, TMEM125, TTC9, CST6, ACOT11, TUBA4A, PERP, ABHD11, BTC, CJB3, TNK1, LRRC1, ARRDC1, ANXA3, C11orf52, TCM4, ADIRF, LPAR5, GJB4, GJB5, MCTP2, TRIM31, HID1, DAPP1, SLPI, MST1R, LY75, CRYBG2, FUCA1, EPHA1, BIK, C1orf210, JUP, DDR1, LRG1, VAMP8, F3. CD9, TNK1, ILDR1, ITGB4, ESRP1, GALNT3, RNF223 MPZL2, EPCAM, B3GNT3, ST14, PTK7, GPR87, KCNK6, UPK2, HSH2D, KLF5, TMPRSS4, FRK, FAM83F, KRT19, TMC4, TC2N, PRRG2, RBM47, TC22, ITGB6, and TMEM125, and wherein the one or more genes identified as negatively correlated with EMT Up signatures are selected from among PTCH2, TET3, AUNIP, E2F2, BEND3, CCSAP, INPP5J, RMND5B, PHF8, RAB11FIP4, OTUD3, KCNJ11, ZBTB39, STRBP, FZD3, SNK1, STRBP, PPFIA3, ADGRL1, FEM1A, MYCL, CHTOP, TICRR, CDS1, LHX4, PCNT, TCLD2, HDHD3, STRBP, CAMSAP3, C2orf15, DENND1C, IQANK1, MARVELD3, ZDHHC23, LNX2, ESRP2, BSPRY, LLGL2, SKY, CRB3, MAP7, MYH14, ERBB3, KDF1, OVOL1, HSD11B2, GLS2, MARVELD2, ARHGAP8, PRR5, CDS1, AP1Ar, EPB41, TET3, ESRP2, GAN, CDC42BPG, POU2F1, DDI2, ARHGAP8, STRBP, RREB1, LRRC8B, LLGL2, GRTP1, HOOK1, BSPRY, RDH13, SPATA2L, MCM9, PRR5, and RDH13.
  6. 38 . The method of claim 5 , further comprising: identifying the cancer as an EMT cancer by detecting in the cancer or in the subject the presence of one or more of the following metabolites: stearoylcarnitine, C16.0.SM, betaine, palmitoylcarnitine, adenosine, 6.phosphogluconate, 1.methylnicotinamide, anthranilic.acid, carnosine, and/or sorbitol.
  7. 39 . A method for identifying and treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method comprising: (a) detecting the expression in the cancer of one or more genes identified as positively correlated with CDS2 dependency selected from among PKP3, CDS1, MAL2, ELF3, IRF6, PATJ, CDH1, MAP7, ARHGEF16, ARHGEF5, TNK1, CNKSR1, ARHGAP8, CLDN4, IQANK1, CDH3, OVOL1, C11orf52, GRB7, GRHL2, C6orf132, MARVELD3, ESRP1, MPZL2, CHMP4C, TMEM125, TACSTD2, MYO5B, PRSS22, S100A14, SRP2, CRB3, EPCAM, RAB25, CLBC, TMEM184A, CLDN7, PRSS8, PRRG2, and SFN; and (b) administering to the subject one or more agents capable of inhibiting CDS2 expression or activity, thereby identifying and treating the subject having the EMT cancer.
  8. 40 . The method of claim 39 , wherein the one or more genes identified as positively correlated with CDS2 dependency is detected in the cancer below a reference value, wherein the reference value is determined by comparison to an appropriate control sample lacking the EMT cancer.
  9. 41 . The method of claim 39 , wherein the one or more genes comprises CDS1.
  10. 42 . A method for identifying and treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method comprising: (a) detecting in the subject one or more metabolites identified as negatively correlated with CDS2 dependency, wherein the one or more metabolites is selected from among oxalate, C38.4.PC, AMP, C40.6.PC, C56.5.TAG, C50.0.TAG, trimethylamine.N.oxide, C58.7.TAG, C56.7.TAG, C36.4.PC.A, UMP, C22.1.SM, dCMP, C56.6.TAG, C58.6.TAG, C36.4.PC.B, C58.8.TAG, cytidine, CMP, C38.6.PC, alpha.glycophosphate, arachidonyl_carnitine, C38.5.PC, and C58.8.TAG; and (b) administering to the subject one or more agents capable of inhibiting CDS2 expression or activity, thereby identifying and treating the subject having the EMT cancer.
  11. 43 . The method of claim 42 , wherein the one or more metabolites identified as negatively correlated with CDS2 dependency is detected in the subject above a reference value, wherein the reference value is determined by comparison to an appropriate control subject or sample lacking the EMT cancer.
  12. 44 . The method of claim 5 , wherein the administering step is performed prior to, concurrently with, or after a primary cancer treatment.
  13. 45 . The method of claim 5 , further comprising: detecting cancer cells that express a mesenchymal signature after the administering step and comparing to the number of cancer cells expressing a mesenchymal signature before the administering step, wherein the treatment is identified as efficacious in the subject if the number of tumor cells expressing a mesenchymal signature decreases.
  14. 46 . The method of claim 5 , wherein the one or more agents are one or more small molecules that reduce the activity or expression of CDS2 or the one or more genes.
  15. 47 . The method of claim 46 , wherein the one or more small molecules is capable of binding to the active site of CDS2, wherein the active site is an antagonistic analog of 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid, or an anionic phospholipid end product or analog thereof, or phosphatidylinositol-(4,5)-bisphosphate or derivatives thereof.
  16. 48 . The method of claim 46 , wherein the one or more small molecules is a small molecule degrader capable of degrading CDS2 or the one or more genes.
  17. 49 . The method of claim 5 , wherein the one or more agents is an RNAi or an antisense oligonucleotide (ASO).
  18. 50 . The method of claim 5 , wherein the one or more agents is a transcriptional repressor system comprising a DNA binding element linked to or otherwise capable of complexing with a transcriptional repressor and configured to bind an enhancer of CDS2 or configured to bind the one or more genes.
  19. 51 . The method of claim 5 , wherein the one or more agents is an epigenetic modification polypeptide comprising a DNA binding element linked to or otherwise capable of associating with an epigenetic modification domain such that binding of the DNA binding element at a target sequence on gDNA results in one or more epigenetic modifications by the epigenetic modification domain that decreases expression of CDS2 or the one or more genes.
  20. 52 . The method of claim 51 , wherein the DNA binding element comprises a zinc finger protein or a DNA-binding domain thereof, a TALE protein or a DNA-binding domain thereof, or a Cas nuclease protein or a DNA-binding domain thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATION The present application is a continuation application of International Application No. PCT/US2024/019759, filed on Mar. 13, 2024, which is related to and claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application No. 63/451,800, entitled “Treatment of Cancers having a Drug-Resistant Mesenchymal Cell State,” filed Mar. 13, 2023. The entire content of the aforementioned patent applications is incorporated herein by this reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been filed electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Sep. 12, 2025, is named “BI11045_SL.xml” and is 18,200 bytes in size. TECHNICAL FIELD The subject matter disclosed herein is generally directed to methods of treating cancers having a drug-resistant mesenchymal cell state by targeting novel vulnerabilities in tumor cells expressing a mesenchymal signature. BACKGROUND Epithelial-to-mesenchymal transition (EMT) occurs in cancer when a well differentiated, epithelial cancer cell undergoes a transcriptional rewiring and evolves into a more mesenchymal, poorly differentiated state. EMT in cancer has been associated with enhanced capacity for invasion as well as drug resistance to both targeted therapy agents as well as standard chemotherapy regimens. Recent single-cell RNA sequencing studies have led to an increased appreciation for the heterogeneous existence of mesenchymal cell states within adenocarcinomas at baseline, before treatment. Moreover, in the context of chemotherapy treatment, these mesenchymal cell states become enriched in the drug-resistant population of cells left after completion of therapy. Moreover, profound plasticity and EMT is postulated to occur in the context of therapy, leading to drug-resistant mesenchymal cell states. Identifying novel strategies to target these mesenchymal cell states may have profound implications for cancer therapy. Citation or identification of any document in this application is not an admission that such a document is available as prior art to the present disclosure. SUMMARY In one aspect, the instant disclosure provides a method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method involving administering to the subject YM-155 or a derivative thereof, thereby treating the subject having the EMT cancer. Another aspect of the disclosure provides a method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method involving administering to the subject niclosamide or a derivative thereof, thereby treating the subject having the EMT cancer. An additional aspect of the disclosure provides a method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method involving administering to the subject one or more of bis.maltolato.oxovanadium.IV, digoxin, GS.9973, LE.135, thiram, butamben, talazoparib, cycloheximide, X2.3.DCPE, epirubicin, etoposide.phosphate, verubulin, indisulam, tasisulam, vinflunine, vindesine, dinaciclib, streptozotocin, Olaparib, PHA.680632, entinostat, SB.225002, oligomycin.A, ouabain, STF.31, lovastatin, LY2183240, BI.2536, SCH.79797, vincristine, homoharringtonine, tipifarnib, tivantinib, methotrexate, axitinib, BRD.K97651142, gossypol, and/or phloretin, thereby treating the subject having the EMT cancer. Another aspect of the disclosure provides a method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method involving administering to the subject one or more agents capable of inhibiting CDS2 expression or activity, thereby treating the subject having the EMT cancer. An aspect of the disclosure provides a method for treating a subject having a cancer capable of an epithelial-to-mesenchymal transition (an EMT cancer), the method involving administering to the subject one or more agents capable of inhibiting the expression or activity of CDS2, ELMO2, ITGAV, AP1M1, FERMT2, CHMP4B, PTK2, ITGB5, PRKAR1A, ACTR1A, SRF, ZEB1, MTOR, DNM1L PSMB7, MOB4, TEAD1, DOCK5, ACTR3, BCAR1, UFM1, TIPARP, ILK, RSU1, WWTR1, NCKAP1, ATP6V1C1, MYH9, FOSL1, LIMS1, GNB1, EFR3A, ARHGEF7, WDR7, PKN2, CEMIP2, TEAD1, CTDNEP1, MARK3, VCL, CDC42, BCAR1, EGLN1, UFM1, GPX4, and/or CRK, thereby treating the subject having the EMT cancer. In some embodiments, the method further includes identifying the cancer as an EMT cancer by a step involving detecting in the cancer the expression of one or more genes shown in any of FIGS. 3A-3C as positively correlated with EMT Down signatures (e.g., PTPN6, ILDR1, TSTD1, LCN2, MYO6, MFSD6, AMN, DDR1, PPL, C2orf15, AREG, CD9, FAM160A1, ENPP5, CD24, SMIM22, RAB25, PRRG2, CLDN4, RNF223, PLA2G4F, LLMO3, MAP7, MAL2, CBLC, KRTCAP3, MACC1, F11R, SPINT1, CNKSR1, CGN, IRF6, ESRP2, MPZL