IP Library › Granted Patent US 11,447,830
Granted Patent B2
US 11,447,830 · App. 16/490,588 · Granted Sep 20, 2022

Gene signatures to predict drug response in cancer

Inventors: Shiaw-Yih Lin (Bellaire, TX); Daniel McGrail (Houston, TX); Gordon Mills (Houston, TX)
Assignee: Board of Regents, The University of Texas System
C12Q1/6886G16B40/10G16H50/30C12Q2600/106C12Q2600/118C12Q2600/158
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Quick Facts
Patent No.
US 11,447,830
App. No.
16/490,588
Granted
Sep 20, 2022
Kind
B2
Abstract

Methods for identifying and treating cancers that are DNA repair, such as homologous recombination (HR) repair, defective or sensitive to PARP inhibitors or platinum-based therapy. In some aspects, DNA repair, such as HR repair, defective cancers are treated with a PARP inhibitor therapy or cisplatin. Methods for sensitizing cancers to a PARP inhibitor therapy are also provided.

Claims (34)

1. A method of treating a cancer in a subject comprising:

(a) determining the expression levels of at least genes ZNF880, CAPN13, LYAR, and NPM3 from the group consisting of SNX10, ECI2, DBN1, TNFRSF10B, NPM3, CATSPER1, PRMT3, FAM216A, LYAR, NOP16, THG1L, LOC439949, TMA16, GEMIN4, HAUS6, SFXN4, SAAL1, NUP160, ESD, TSEN15, KIAA1704, HSPA4, SFXN1, NAT10, C11orf48, TSEN2, HEATR2, GEMIN5, IMPDH2, NOC3L, ERLIN1, C1QBP, EIF3M, MTHFD1L, MTX3, MRPS27, PPRC1, TCOF1, IDE, RNF2, WDR75, NAA15, DDX21, RARS, ALG8, BOLA3, EARS2, FAF2, MRPL42, ATIC, NUP37, RPL36, GNB2L1, NPBWR1, GALNTL5, LOC729173, LOC441461, KALRN, ADCY2, MTHFR, MS4A7, RNF186, IRF4, WBSCR17, CLEC7A, WDTC1, PRKG2, OSTalpha, DUSP18, LOC100652843, FAIM2, TNNI2, SEZ6, LOC285556, KCNQ1, KLF8, VPS13D, NR0B2, TMEM86A, DCAF5, SOS2, CAPN9, RIPK3, TPRXL, CELF4, ATP6V1E1, ZBTB7C, CATSPERB, CAPN13, MMEL1, ELF5, C2orf54, DVL3, SIRT2, LOC641518, IL12RB2, CBFA2T2, LINC00518, OSBPL2, SH3GLB1, CHMP4B, HSD11B2, ACVR1C, TMEM61, DLL3, CXCL17, SLC44A4, RNF183, KLK8, RIIAD1, ATP7A, GJB1, BCAS1, SCGN, TTC3, IGSF11, LOC440335, LOC645591, C4orf3, LRRC31, ADAM12, BHLHE41, RNASE1, PPP1R3B, LOC100505989, CAPN8, C2CD4A, CHGA, ERBB2, NELL1, FAM174B, CALML5, TSC22D3, C9orf152, KLK6, MB, ST6GALNAC1, SFTA2, MUC1, SETBP1, SCG3, PRUNE2, SSPN, CEACAM5, TMEM45B, MAFB, and ZNF880 in a sample comprising cancer cells from said subject;

(b) identifying the subject as having a PARP inhibitor sensitive cancer by calculating a signature score from the expression levels of the genes, wherein a positive signature score identifies the subject as having a PARP inhibitor sensitive cancer; and

(c) administering an effective amount of a PARP inhibitor to said subject identified to have a PARP inhibitor sensitive cancer.

2. The method of claim 1 , wherein the cancer cells are breast cancer cells or ovarian cancer cells.

3. The method of claim 1 , wherein the sample is blood, saliva, urine, or a tissue biopsy.

4. The method of claim 1 , further comprising determining the expression levels of at least 5, 6, 7, 8, 9 or 10 genes.

5. The method of claim 1 , wherein determining the expression levels comprises performing RT-PCR, hybridization, transcriptome analysis, a Northern blot, a Western blot, RNA sequencing, or an ELISA.

6. The method of claim 1 , further comprising administering to the subject at least a second anti-cancer therapy.

7. The method of claim 6 , wherein the at least a second anti-cancer therapy is chemotherapy, immunotherapy, surgery, radiotherapy, or biotherapy.

8. The method of claim 6 , wherein the subject is treated with a PARP inhibitor and the PARP inhibitor and the at least a second anti-cancer therapy are administered simultaneously.

9. The method of claim 6 , wherein the PARP inhibitor is administered to the subject prior to the at least a second anti-cancer therapy.

10. The method of claim 6 , wherein the at least a second anti-cancer therapy is a PKCβ inhibitor.

11. The method of claim 10 , wherein the PKCβ inhibitor is Enzastaurin.

12. The method of claim 1 , wherein the PARP inhibitor is talazoparib, olaparib, ABT-888, Iniparib, BMN 673, Rucaparib, AG14361, INO-1001, A-966492, PJ34, or MK-4827.

13. The method of claim 1 , wherein determining the expression levels comprises determining expression levels relative to a healthy control, and determining relative fold changes, and step (b) further comprises determining gene expression z-scores from relative gene fold changes.

14. The method of claim 13 , wherein determining the signature score comprises summing the product of each gene expression z-score multiplied by its corresponding refined coefficient, wherein genes SNX10, ECI2, DBN1, TNFRSF10B, NPM3, CATSPER1, PRMT3, FAM216A, LYAR, NOP16, THG1L, LOC439949, TMA16, GEMIN4, HAUS6, SFXN4, SAAL1, NUP160, ESD, TSEN15, KIAA1704, HSPA4, SFXN1, NAT10, C11orf48, TSEN2, HEATR2, GEMIN5, IMPDH2, NOC3L, ERLIN1, C1QBP, EIF3M, MTHFD1L, MTX3, MRPS27, PPRC1, TCOF1, IDE, RNF2, WDR75, NAA15, DDX21, RARS, ALG8, BOLA3, EARS2, FAF2, MRPL42, ATIC, NUP37, RPL36, and GNB2L1 have a refined coefficient of positive 1,

and genes NPBWR1, GALNTL5, LOC729173, LOC441461, KALRN, ADCY2, MTHFR, MS4A7, RNF186, IRF4, WBSCR17, CLEC7A, WDTC1, PRKG2, OSTalpha, DUSP18, LOC100652843, FAIM2, TNNI2, SEZ6, LOC285556, KCNQ1, KLF8, VPS13D, NR0B2, TMEM86A, DCAF5, SOS2, CAPN9, RIPK3, TPRXL, CELF4, ATP6V1E1, ZBTB7C, CATSPERB, CAPN13, MMEL1, ELF5, C2orf54, DVL3, SIRT2, LOC641518, IL12RB2, CBFA2T2, LINC00518, OSBPL2, SH3GLB1, CHMP4B, HSD11B2, ACVR1C, TMEM61, DLL3, CXCL17, SLC44A4, RNF183, KLK8, RIIAD1, ATP7A, GJB1, BCAS1, SCGN, TTC3, IGSF11, LOC440335, LOC645591, C4orf3, LRRC31, ADAM12, BHLHE41, RNASE1, PPP1R3B, LOC100505989, CAPN8, C2CD4A, CHGA, ERBB2, NELL1, FAM174B, CALML5, TSC22D3, C9orf152, KLK6, MB, ST6GALNAC1, SFTA2, MUC1, SETBP1, SCG3, PRUNE2, SSPN, CEACAM5, TMEM45B, MAFB, and ZNF880 have a refined coefficient of −1.

15. The method of claim 1 , wherein step (a) comprises determining the expression levels of at least 40 genes.

16. The method of claim 15 , wherein the at least 40 genes are ALG8, C1QBP, CAPN13, CATSPERB, CEACAM5, CHMP4B, DVL3, ERBB2, ESD, GEMIN4, GJB1, HEATR2, HSD11B2, IDE, KCNQ1, LRRC31, LYAR, MB, MMEL1, MRPS27, MTHFR, NAT10, NPM3, NUP37, OSTalpha, PPRC1, PRKG2, PRMT3, RARS, RNF183, RNF2, SCGN, SEZ6, SFTA2, SOS2, TCOF1, TMEM61, TSEN15, WDTC1, and ZNF880.

17. The method of claim 1 , wherein step (a) comprises determining the expression levels of at least 30 genes.

18. The method of claim 17 , wherein the at least 30 genes are NPM3, LYAR, GEMIN4, TSEN15, KIAA1704, NAT10, HEATR2, C1QBP, RARS, ALG8, NUP37, ATP7A, DDX21, MTHFR, WDTC1, PRKG2, OSTalpha, SEZ6, KCNQ1, CATSPERB, CAPN13, DVL3, HSD11B2, RNF183, SCGN, ERBB2, LRRC31, MB, SFTA2, and ZNF880.

19. The method of claim 1 , wherein step (a) comprises determining the expression levels of at least 20 genes.

20. The method of claim 19 , wherein the at least 20 genes selected from the group consisting of ALG8, CAPN13, ESD, TSEN15, GEMIN4, GJB1, HEATR2, IDE, KCNQ1, LYAR, NPM3, OSTalpha, PPRC1, RARS, RNF183, SCGN, SEZ6, SFTA2, WDTC1, and ZNF880.

21. The method of claim 1 , wherein step (a) comprises determining the expression levels of at least 10 genes.

22. The method of claim 21 , wherein the at least 10 genes are ALG8, CAPN13, ESD, HEATR2, IDE, LYAR, MB, NPM3, THG1L, and ZNF880.

23. The method of claim 1 , further comprising measuring the expression of IDE.

24. The method of claim 1 , further comprising measuring the expression of IDE and GJB1.

25. The method of claim 1 , further comprising measuring the expression of IDE, GJB1 and PPRC1.

26. The method of claim 1 , further comprising measuring the expression of IDE, GJB1, PPRC1 and GEMIN4.

27. The method of claim 1 , further comprising measuring the expression of IDEGJB1, WDTC1, SCGN, and PPRC1.

28. The method of claim 1 , further comprising measuring the expression of PPRC1, GJB1 OSTalpha and RARS.

29. The method of claim 1 , further comprising measuring the expression of IDESFTA1, SCGN, GHB1, and EST.

30. The method of claim 1 , wherein the expression levels are quantile-normalized and median polished.

Assignments (2)
CONFIRMATORY LICENSE Recorded Mar 30, 2022
From: UNIVERSITY OF TX MD ANDERSON CAN CTR
To: UNITED STATES GOVERNMENT
Reel/Frame 059543/0841 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 24, 2019
From: LIN, SHIAW-YIH; MCGRAIL, DANIEL; MILLS, GORDON
To: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
Reel/Frame 050476/0986 →
Continuity (2)
Provisional Application 62466829 · Mar 3, 2017
Related Publication 20200017918A1 · Jan 16, 2020
Cited By (1)
US 12,228,574