# US 2017/0283885 A1 · Algorithms for gene signature-based predictor of sensitivity to mdm2 inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2017/0283885 A1 - Document ID: US20170283885A1 - Status: Published application - Kind: A1 - Application number: 15/510,892 - Filed: 2015-10-09 - Published: 2017-10-05 - Earliest claimed: 2014-10-09 - Assignees: Daiichi Sankyo Company, Limited - Applicants: Daiichi Sankyo Company, Limited - Inventors: Ngai-chiu Archie TSE; Kenji NAKAMARU; Koichi TAZAKI; Kenji WATANABE; Takahiko SEKI - Web page: https://patentgrep.com/patent/US20170283885A1 ## CPC - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) - A61K 31/499: Spiro-condensed pyrazines or piperazines - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - G01N 33/575: for cancer - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/156: Polymorphic or mutational markers - C12Q 2600/158: Expression markers - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Provided are gene signatures that are predictive of the sensitivity of a cancer or tumor to an MDM2i or an antagonist of the MDM2-p53 interaction. Differentially expressed genes in the provided gene signatures serve as biomarkers for determining and assessing the sensitivity of cancer and tumor samples to treatment or therapy with an MDM2i. Also provided are methods of determining MDM2i sensitivity of a test sample such as different cancer and tumor types and subtypes, based on the expression of genes in the MDM2i sensitive gene signatures in reference samples and the test sample even if all of the MDM2i sensitivities of the reference samples are unknown, and treating individuals with an MDM2i if their cancers are determined to be MDM2i-sensitive, based on the practice of the described methods. TP53 gene and p53 protein status can also be determined for the samples undergoing analysis for MDM2i sensitivity. ## Claims ### Claim 1 A method of predicting the sensitivity of a subject's cancer or tumor to MDM2i treatment, comprising measuring the levels of expression of at least three genes selected from the group consisting of RPS27L, FDXR, CDKN1A, AEN, RRM2B, SESN1, TRIAP1, DDB2, CCNG1, XPC, RPL22L1, C12orf5, PPM1D, BAX, BLOC1S2, PHLDA3, PHF23, ZMAT3, FBX022, SPATA18, MDM2, CYFIP2, C1QBP, SPAG7, MAA1967, EDA2R, TNFRSF10B, TP53INP1, SCO1, ZNF828, CLN8, UBFD1, ACTA2, SLC25A11, WDR61, ZSWIM7, NCRNA00188, SPCS1, SMAD4, CCRN4L, PHB2, GRSF1, GAMT, PPID, CNO, OSTC, PSMB6, TMEM131, TYMS, UTP3, LEPROTL1, FOXRED2, EIF4E, RCBTB1, FAM119A, GDF15, MFSD5, BBC3, C19orf60, CNPY2, TM7SF3, ARLSA, FAM98A, TXNL1, ASTN2, ATP5G3, CCDC135, PKD2, SSTR4, LOC731139, ART5, PEBP1, COX18, UBE2G1, ACADS, RAD51C, TARBP2, ARSB, STX8, SLC35B4, NUDT9, MED31, POLH, POLDIP3, A4GNT, RAB3A, SALL1, MAP2K4, ME2, GREB1, FXN, MRPL44, MRPS23, C17orf81, PAPPA2, HDDC2, SLC22A13, FBN3, MFAP3L, C18orf55, ACADSB, TYRO3, TSPAN14, LSMD1, FAM193A, CDK2, DIMT1L, SLC25A30, TTTY11, DCP1B, PDE12, EIF2D, LAMA1, TIMM22, COX10, GLDC, UXS1, CDH20, PDYN, LLGL1, GABARAP, PFAS, PRKY, PRDX3, C17orf71, CNNM2, PCDP1, MED11, USF1, LONP1, TEX19, IFFO1, NAP1L1, FAS, VPS25, TP53, TECTB, KIAA1467, MAPK12, CRADD, LOC643659, NDUFB2, TRAPPC1, HHAT, MRPL19, C18orf32, TSFM, NOP14, MPDU1, GPR84, UBA52, ISCU, IL3, METRN, KCTD7, ZNF425, GDPD1, LOC100129857, PDLIM2, ZNF746, SLC20A1, TNFSF9, EIF1AY, PRTG, TXN2, ORICH2, EIF1B, MLF2, SNX10, MRPL51, ANKRD52, TMEM93, C12orf26, POLR3K, C21orf57, DISC1, and PRPF8 in a cancer or tumor sample obtained from the subject. ### Claim 2 (depends on 1) A method of predicting the sensitivity of a subject's cancer or tumor to MDM2i treatment, comprising: a) measuring the levels of expression of at least three genes selected from the genes listed in claim 1 in a cancer or tumor sample obtained from the subject; and b) determining if the cancer or tumor sample has a wild-type TP53 gene. ### Claim 3 (depends on 1) The method according to claim 1, wherein the at least three genes are all of the genes in claim 1. ### Claim 4 (depends on 1) The method according to claim 1, wherein the genes are selected from the group consisting of are BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 5 (depends on 1) The method according to claim 1, wherein the genes are selected from the group consisting of are RPS27L, FDXR, CDKN1A and AEN. ### Claim 6 (depends on 1) The method according to claim 1, wherein measuring the levels of expression of genes comprises measuring the levels of expression of mRNA. ### Claim 7 (depends on 1) The method according to claim 1, wherein measuring the levels of expression of the genes comprises measuring the levels of expression of proteins encoded by the genes. ### Claim 8 (depends on 1) The method according to claim 1, wherein the MDM2i is a spirooxindole derivative, an indole derivative, a pyrrolidine-2-carboxamide derivative, a pyrrolidinone derivative, an isoindolinone derivative, or an imidazothiazole derivative. ### Claim 9 (depends on 1) The method according to claim 1, wherein the MDM2i is Compound A or a salt thereof, Compound B or a salt thereof, CGM097, RG7388, MK-8242 (SCH900242), MI-219, MI-319, MI-773, MI-888, Nutlin-3a, RG7112 (R05045337), TDP521252, TDP665759, PXN727, or PXN822. ### Claim 10 (depends on 1) The method according to claim 1, wherein the MDM2i is Compound A or a salt thereof, or Compound B or a salt thereof. ### Claim 11 (depends on 1) A method of treating an individual having a cancer or tumor, comprising: c) assessing the sensitivity of a subject's cancer or tumor to MDM2i treatment, comprising measuring the levels of expression of at least three genes selected from the genes listed in claim 1 in a cancer or tumor sample obtained from the subject; and d) if the assessment indicates that the cancer or tumor is sensitive to the MDM2i, administering to the individual an effective amount of an MDM2i to treat the cancer or tumor. ### Claim 12 (depends on 1) A method of treating an individual having a cancer or tumor, comprising: e) assessing the sensitivity of a subject's cancer or tumor to MDM2i treatment, comprising measuring the levels of expression of at least three genes selected from the genes listed in claim 1 in a cancer or tumor sample obtained from the subject; f) determining if the cancer or tumor has a wild-type TP53 gene; and g) if the assessment a) indicates that the cancer or tumor is sensitive to the MDM2i and the cancer or tumor specimen has a wild-type TP53 gene, administering to the individual an effective amount of an MDM2i to treat the cancer or tumor. ### Claim 13 (depends on 11) The method according to claim 11, wherein the at least three genes are all of the genes in claim 11. ### Claim 14 (depends on 11) The method according to claim 11, wherein the genes are selected from the group consisting of BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 15 (depends on 11) The method according to claim 11, wherein the genes are selected from the group consisting of RPS27L, FDXR, CDKN1A and AEN. ### Claim 16 (depends on 11) The method according to claim 11, wherein the levels of expression of genes is the expression of mRNA. ### Claim 17 (depends on 11) The method according to claim 11, wherein the levels of expression of genes is the expression of protein encoded by the genes. ### Claim 18 (depends on 11) The method according to claim 11, wherein the MDM2i is a spirooxindole derivative, an indole derivative, a pyrrolidine-2-carboxamide derivative, a pyrrolidinone derivative, an isoindolinone derivative, or an imidazothiazole derivative. ### Claim 19 (depends on 11) The method according to claim 11, wherein the MDM2i is Compound A or a salt thereof, Compound B or a salt thereof, CGM097, RG7388, MK-8242 (SCH900242), MI-219, MI-319, MI-773, MI-888, Nutlin-3a, RG7112 (R05045337), TDP521252, TDP665759, PXN727, or PXN822. ### Claim 20 (depends on 11) The method according to claim 11, wherein the MDM2i is Compound A or a salt thereof or Compound B or a salt thereof. ### Claim 21 (depends on 1) A gene signature for predicting the sensitivity of a subject's cancer or tumor to MDM2i treatment consisting of at least three genes selected from the genes listed claim 1. ### Claim 22 (depends on 21) The gene signature according to claim 21, wherein the genes are selected from the group consisting of are BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 23 (depends on 21) The gene signature according to claim 21, wherein the genes are selected from the group consisting of are RPS27L, FDXR, CDKN1A and AEN. ### Claim 24 (depends on 21) The gene signature according to claim 21, wherein the MDM2i is a spirooxindole derivative, an indole derivative, a pyrrolidine-2-carboxamide derivative, a pyrrolidinone derivative, an isoindolinone derivative, or an imidazothiazole derivative. ### Claim 25 (depends on 21) The gene signature according to claim 21, wherein the MDM2i is Compound A or a salt thereof, Compound B or a salt thereof, CGM097, RG7388, MK-8242 (SCH900242), MI-219, MI-319, MI-773, MI-888, Nutlin-3a, RG7112 (R05045337), TDP521252, TDP665759, PXN727, or PXN822. ### Claim 26 (depends on 1) A composition comprising a plurality of nucleic acid probes for detecting at least three genes listed claim 1. ### Claim 27 (depends on 26) The composition according to claim 26, wherein the at least three genes are all of the genes in claim 26. ### Claim 28 (depends on 26) The composition according to claim 26, wherein the at least three genes are selected from the group consisting of BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 29 (depends on 26) The composition according to claim 26, wherein the at least three genes are selected from the group consisting of RPS27L, FDXR, CDKN1A and AEN. ### Claim 30 (depends on 26) The composition according to claim 26, wherein the plurality of nucleic acid probes comprises an array or a microarray. ### Claim 31 (depends on 1) A kit comprising reagents for the detection of at least three genes listed claim 1, which are indicative of sensitivity to an MDM2i and instructions for use. ### Claim 32 (depends on 1) A kit for predicting sensitivity of a cancer or tumor sample to an MDM2i, said kit comprising nucleic acid probes that specifically bind to nucleotide sequences corresponding to at least three genes listed claim 1, and a means of labeling the nucleic acids. ### Claim 33 (depends on 1) A kit for predicting sensitivity of a cancer or tumor sample to an MDM2i, said kit comprising antibodies or ligands that specifically bind to polypeptides encoded by at least three genes listed claim 1, and a means of labeling the antibodies or ligands that specifically bind to polypeptides or peptides encoded by the genes. ### Claim 34 (depends on 31) The kit according to claim 31, wherein the at least three genes are all of the genes in claim 31. ### Claim 35 (depends on 31) The kit according to claim 31, wherein the at least three genes are selected from the group consisting of BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 36 (depends on 31) The kit according to claim 31, wherein the at least three genes are selected from the group consisting of RPS27L, FDXR, CDKN1A and AEN. ### Claim 37 (depends on 31) The kit according to claim 31, wherein the MDM2i is a spirooxindole derivative, an indole derivative, a pyrrolidine-2-carboxamide derivative, a pyrrolidinone derivative, an isoindolinone derivative, or an imidazothiazole derivative. ### Claim 38 (depends on 31) The kit according to claim 31, wherein the MDM2i is Compound A or a salt thereof, Compound B or a salt thereof, CGM097, RG7388, MK-8242 (SCH900242), MI-219, MI-319, MI-773, MI-888, Nutlin-3a, RG7112 (R05045337), TDP521252, TDP665759, PXN727, or PXN822. ### Claim 39 (depends on 31) The kit according to claim 31, wherein the MDM2i is Compound A or a salt thereof or Compound B or a salt thereof. ### Claim 40 (depends on 1) A method for predicting the sensitivity of a subject's cancer or tumor to MDM2i treatment, comprising: a) measuring the levels of expression of genes comprising at least three genes selected from the genes listed in claim 1 in a cancer or tumor sample obtained from the subject; b) scoring the levels of expression of the genes obtained in step a) to obtain the subject's sensitivity score; c) measuring the levels of expression of the genes in plurality of cancer samples or tumor samples, wherein sensitivities to MDM2i treatment of at least a part of the samples are unknown; d) scoring the levels of expression of the genes obtained in step c) to obtain a reference score in each sample and determining a threshold based on the distribution of the reference scores; and e) predicting that the subject is sensitive to MDM2i treatment if the subject's sensitivity score is over the threshold and the subject is resistant to MDM2i treatment if the subject's sensitivity score is under the threshold. ### Claim 41 (depends on 40) The method according to claim 40, further comprising: f) predicting that the subject is sensitive to MDM2i treatment if the subject that is predicted as resistant in step e) shows an MDM2 overexpression. ### Claim 42 (depends on 40) The method according to claim 40, further comprising: f) predicting that the subject is sensitive to MDM2i treatment if the subject that is predicted as resistant in step e) shows an MDM2 overexpression and has wild type TP53 genes. ### Claim 43 (depends on 41) The method according to claim 41, wherein the MDM2 overexpression is caused by an amplification of MDM2 genes in the genome of the subject. ### Claim 44 (depends on 40) The method according to claim 40, wherein steps b) and d) comprise summing the normalized scores (z-scores) of the levels of the gene expression to obtain the subject's sensitivity score. ### Claim 45 (depends on 44) The method according to claim 44, wherein the threshold in e) ranges between −0.2 and 0.5. ### Claim 46 (depends on 40) The method according to claim 40, wherein the threshold in e) ranges between the values of the third quartile and the maximum of the reference scores of TP53 mutant samples among the samples; or between the values of the first quartile and the minimum of the reference scores of TP53 wild type samples among the samples. ### Claim 47 (depends on 40) The method according to claim 40, wherein the threshold is determined based on Receiver Operating Characteristic (ROC) plots optionally by conducting leave-one-out cross-validation (LOOCV) analysis. ### Claim 48 (depends on 47) The method according to claim 47, wherein the threshold falls within the Youden Index±0.3 of the Receiver Operating Characteristic (ROC) curve. ### Claim 49 (depends on 40) The method according to claim 40, wherein the threshold is determined from the shape of the distribution of the reference scores by using a binalization algorithm. ### Claim 50 (depends on 40) The method according to claim 40, wherein the threshold is determined by Gaussian Mixture model. ### Claim 51 (depends on 50) The method according to claim 50, wherein the threshold is determined based on the ratios of the number of the genes indicating the subject as sensitive to that of the genes indicating the subject as resistant by using two Gaussian distribution in Gaussian Mixture model in step d). ### Claim 52 (depends on 51) The method according to claim 51, wherein the threshold in step e) ranges between the values of the third quartile and the maximum of the ratios of the TP53 mutant samples among the samples; or between the values of the first quartile and the minimum of the ratios of the TP53 wild type samples among the samples. ### Claim 53 (depends on 40) The method according to claim 40, wherein the at least three genes are all of the genes in claim 40. ### Claim 54 (depends on 40) The method according to claim 40, wherein the genes are selected from the group consisting of BAX, C1QBP, FDXR, GAMT, RPS27L, SLC25A11, TP53, TRIAP1, ZMAT3, AEN, C12orf5, GRSF1, EIF2D, MPDU1, STX8, TSFM, DISC1, SPCS1, PRPF8, RCBTB1, SPAG7, TIMM22, TNFRSF10B, ACADSB, DDB2, FAS, GDF15, GREB1, PDE12, POLH, C19orf60, HHAT, ISCU, MDM2, MED31, METRN, PHLDA3, CDKN1A, SESN1 and XPC. ### Claim 55 (depends on 40) The method according to claim 40, wherein the genes selected from the group consisting of RPS27L, FDXR, CDKN1A and AEN. ### Claim 56 (depends on 40) The method according to claim 40, wherein the genes selected from the group consisting of RPS27L, FDXR, CDKN1A, AEN and MDM2. ### Claim 57 (depends on 40) The method according to claim 40, wherein measuring the levels of expression of genes comprises measuring the levels of expression of mRNA. ### Claim 58 (depends on 40) The method according to claim 40, wherein measuring the levels of expression of the genes comprises measuring the levels of expression of proteins encoded by the genes. ### Claim 59 (depends on 40) The method according to claim 40, wherein the MDM2i is a spirooxindole derivative, an indole derivative, a pyrrolidine-2-carboxamide derivative, a pyrrolidinone derivative, an isoindolinone derivative, or an imidazothiazole derivative. ### Claim 60 (depends on 40) The method according to claim 40, wherein the MDM2i is Compound A or a salt thereof, Compound B or a salt thereof, CGM097, RG7388, MK-8242 (SCH900242), MI-219, MI-319, MI-773, MI-888, Nutlin-3a, RG7112 (R05045337), TDP521252, TDP665759, PXN727, or PXN822. ### Claim 61 (depends on 60) The method according to claim 60, wherein the MDM2i is Compound A or a salt thereof, or Compound B or a salt thereof. ### Claim 62 (depends on 1) A method for predicting the sensitivities of at least a part of subjects' cancers or tumors to MDM2i treatment, comprising: a′) measuring the levels of expression of genes comprising at least three genes selected from the genes listed in claim 1 in all cancer or tumor samples obtained from all of the subjects whose sensitivities to MDM2i treatment are unknown; b′) scoring the levels of expression of the genes obtained in step a) to obtain all of the subjects' sensitivity scores and determining a threshold based on the distribution of the sensitivity scores; and e) predicting that the subjects whose sensitivity scores are over the threshold are sensitive to MDM2i treatment and that the subjects whose sensitivity scores are under the threshold are resistant to MDM2i treatment. ### Claim 63 (depends on 62) The method according to claim 62, further comprising: f) predicting that subjects are sensitive to MDM2i treatment if the subjects that are predicted as resistant in step e) show an MDM2 overexpression. ### Claim 64 (depends on 62) The method according to claim 62, further comprising: f) predicting that subjects are sensitive to MDM2i treatment if the subjects that are predicted as resistant in step e) show an MDM2 overexpression and have wild type TP53 genes. ### Claim 65 (depends on 63) The method according to claim 63, wherein the MDM2 overexpression is caused by an amplification of MDM2 genes in the genome of the subject. ### Claim 66 (depends on 40) A method for treating a subject having a cancer or tumor, comprising: a) assessing the sensitivity of a subject's cancer or tumor to MDM2i treatment by the method according to claim 40; and b) if the assessment indicates that the cancer or tumor is sensitive to the MDM2i, administering to the subject an effective amount of an MDM2i to treat the cancer or tumor. ### Claim 67 (depends on 40) A pharmaceutical composition for use in treating a cancer or tumor in a subject, wherein the composition comprises an MDM2i, and wherein the subject has been predicted as sensitive to the MDM2i treatment by assessing the sensitivity of a subject's cancer or tumor to the MDM2i treatment by the method according to claim 40.