Assessment of cellular signaling pathway activity using linear combination(s) of target gene expressions

Abstract

The present application mainly relates to specific methods for inferring activity of a cellular signaling pathway in tissue and/or cells of a medical subject based at least on expression levels of one or more target gene(s) of the cellular signaling pathway measured in an extracted sample of the tissue and/or cells of the medical subject, an apparatus comprising a digital compressor configured to perform such methods and a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such methods.

1 . A method for treating a subject diagnosed with cancer, the method comprising:
 selecting, based on determined abnormal operation of a cellular signaling pathway in a tumor sample from the subject, a specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, wherein the determined abnormal operation of the cellular signaling pathway is overactive operation of the cellular signaling pathway and wherein the specific treatment is a signaling pathway inhibitor configured to inhibit the overactive operation of the cellular signaling pathway; and   administering to the subject diagnosed with cancer, in response to the determined abnormal operation of the cellular signaling pathway and selection of the specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, the signaling pathway inhibitor;   wherein the abnormal operation of the cellular signaling pathway in the tumor sample from the subject comprises determining activity of the cellular signaling pathway in a tumor sample from the subject based at least on determined expression levels of the three or more target genes of the cellular signaling pathway, wherein determining activity of the cellular signaling pathway comprises determining a level of a transcription factor (TF) element in the tumor sample from the subject, the TF element controlling transcription of the three or more target genes of the cellular signaling pathway, the determining being based at least in part on evaluating a mathematical model relating expression levels of the three or more target genes of the cellular signaling pathway to the level of the TF element, the model being based at least in part on one or more linear combinations of expression levels of the three or more target genes.   
     
     
         2 . The method of  claim 1 , wherein the cellular signaling pathway comprises a Wnt pathway, an ER pathway, an AR pathway, and/or an HH pathway. 
     
     
         3 . The method of  claim 2 , wherein the signaling pathway inhibitor is a Wnt pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the Wnt pathway, wherein the signaling pathway inhibitor is an ER pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the ER pathway, wherein the signaling pathway inhibitor is an AR pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the AR pathway, and wherein the signaling pathway inhibitor is an HH pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the HH pathway. 
     
     
         4 . The method of  claim 1 , wherein the one or more linear combinations comprises a linear combination of all expression levels of the one or more expression levels provided for the three or more target genes. 
     
     
         5 . The method of  claim 1 , wherein the one or more linear combinations comprise a linear combination including for each of the three or more target genes a weighted term, each weighted term being based on only one expression level of the one or more expression levels provided for the respective target gene. 
     
     
         6 . The method of  claim 1 , wherein the one or more linear combination(s) comprises for each of the three or more target genes a first linear combination of all expression levels of the one or more expression levels provided for the respective target gene, and wherein the model is further based at least in part on a further linear combination including for each of the three or more target genes a weighted term, each weighted term being based on the first linear combination for the respective target gene. 
     
     
         7 . The method of  claim 1 , wherein determining activity of the cellular signaling pathway in the sample based at least on the determined expression levels of the three or more target genes of the cellular signaling pathway comprises:
 determining activity of a Wnt pathway based at least on expression levels of three or more target genes of the Wnt pathway selected from the group comprising: KIAA1199, AXIN2, RNF43, TBX3, TDGF1, SOX9, ASCL2, IL8, SPS, ZNRF3, KLF6, CCND1, DEFA6 and FZD7.   
     
     
         8 . The method of  claim 1 , wherein determining activity of the cellular signaling pathway in the sample based at least on the determined expression levels of the three or more target genes of the cellular signaling pathway comprises:
 determining activity of an ER pathway based at least on expression levels of three or more target genes of the ER pathway selected from the group comprising: CDH26, SGK3, PGR, GREB1, CA12, XBPI, CELSR2, WISP2, DSCAM, ERBB2, CTSD, TFF1 and NRIP1.   
     
     
         9 . The method of  claim 1 , wherein determining activity of the cellular signaling pathway in the sample based at least on the determined expression levels of the three or more target genes of the cellular signaling pathway comprises:
 determining activity of an HH pathway based at least on expression levels of three or more target genes of the HH pathway selected from the group comprising: GLI1, PTCH1, PTCH2, IGFBP6, SPP1, CCND2, FST, FOXL1, CFLAR, TSC22D1, RAB34, S100A9, S100A7, MYCN, FOXM1, GLI3, TCEA2, FYN and CTSL1.   
     
     
         10 . The method of  claim 1 , wherein determining activity of the cellular signaling pathway in the sample based at least on the determined expression levels of the three or more target genes of the cellular signaling pathway comprises:
 determining activity of an AR pathway based at least on expression levels of three or more target genes of the AR pathway selected from the group comprising: KLK2, PMEPA1, TMPRSS2, NKX3 1, ABCC4, KLK3, FKBPS, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR and EAF2.   
     
     
         11 . The method of  claim 7 , wherein the determining is further based on expression levels of at least one target gene of the Wnt pathway selected from the group comprising: NKD1, OAT, FAT1, LEF1, GLUL, REG1B, TCF7L2, COL18A1, BMP7, SLC1A2, ADRA2C, PPARG, DKK1, HNF1A and LECT2. 
     
     
         12 . The method of  claim 8 , wherein the determining is further based on expression levels of at least one target gene of the ER pathway selected from the group comprising: AP1B1, ATPSJ, COL18A1, COX7A2L, EBAG9, ESR1, HSPB1, IGFBP4, KRT19, MYC, NDUFV3, PISD, PRDM15, PTMA, RARA, SOD1 and TRIM25. 
     
     
         13 . The method of  claim 9 , wherein the determining is further based on expression levels of at least one target gene of the HH pathway selected from the group comprising: BCL2, FOXA2, FOXF1, H19, HHIP, IL1R2, JAG2, JUP, MIF, MYLK, NKX2.2, NKX2.8, PITRM1 and TOM1. 
     
     
         14 . The method of  claim 10 , wherein the determining is further based on expression levels of at least one target gene of the AR pathway selected from the group comprising: APP, NTS, PLAU, CDKN1A, DRG1, FGF8, IGF1, PRKACB, PTPN1, SGK1 and TACC2. 
     
     
         15 . The method of  claim 1 , wherein the target genes are mRNA direct target genes, wherein the method further comprises calibrating the mathematical model, and wherein the method further comprises:
 constructing a network between the expression levels of the three or more mRNA direct target genes and the activity of the cellular signaling pathway, and   training the network by:
 determining the level of the TF element, the TF element controlling transcription of the three or more mRNA direct target genes of the cellular signaling pathway; 
 determining the activity of the cellular signaling pathway based on the determined level of the TF element; and 
 measuring the nodes representing corresponding probe set nodes of the corresponding three or more mRNA direct target genes. 
   
     
     
         16 . A method for treating a subject diagnosed with cancer, the method comprising:
 selecting, based on determined abnormal operation of a cellular signaling pathway in a tumor sample from the subject, a specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, wherein the determined abnormal operation of the cellular signaling pathway is inactive or underactive operation of the cellular signaling pathway and wherein the specific treatment is a signaling pathway upregulator configured to upregulate the overactive operation of the cellular signaling pathway; and   administering to the subject diagnosed with cancer, in response to the determined abnormal operation of the cellular signaling pathway and selection of the specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, the signaling pathway upregulator;   wherein the abnormal operation of the cellular signaling pathway in the tumor sample from the subject comprises determining activity of the cellular signaling pathway in a tumor sample from the subject based at least on determined expression levels of the three or more target genes of the cellular signaling pathway, wherein determining activity of the cellular signaling pathway comprises determining a level of a transcription factor (TF) element in the tumor sample from the subject, the TF element controlling transcription of the three or more target genes of the cellular signaling pathway, the determining being based at least in part on evaluating a mathematical model relating expression levels of the three or more target genes of the cellular signaling pathway to the level of the TF element, the model being based at least in part on one or more linear combinations of expression levels of the three or more target genes.   
     
     
         17 . The method of  claim 16 , wherein the cellular signaling pathway comprises a Wnt pathway, an ER pathway, an AR pathway, and/or an HH pathway. 
     
     
         18 . The method of  claim 17 , wherein the signaling pathway upregulator is a Wnt pathway upregulator when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the Wnt pathway, wherein the signaling pathway upregulator is an ER pathway upregulator when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the ER pathway, wherein the signaling pathway upregulator is an AR pathway upregulator when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the AR pathway, and wherein the signaling pathway upregulator is an HH pathway upregulator when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the HH pathway. 
     
     
         19 . A method for treating a subject diagnosed with cancer, the method comprising:
 selecting, based on determined abnormal operation of a cellular signaling pathway in a tumor sample from the subject, a specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, wherein the determined abnormal operation of the cellular signaling pathway is overactive operation of the cellular signaling pathway and wherein the specific treatment is a signaling pathway inhibitor configured to inhibit the overactive operation of the cellular signaling pathway, wherein the cellular signaling pathway is one or more of a Wnt pathway, an ER pathway, an AR pathway, and an HH pathway; and   administering to the subject diagnosed with cancer, in response to the determined abnormal operation of the cellular signaling pathway and selection of the specific treatment configured to remedy the determined abnormal operation of the cellular signaling pathway, the signaling pathway inhibitor, wherein the signaling pathway inhibitor is a Wnt pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the Wnt pathway, wherein the signaling pathway inhibitor is an ER pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the ER pathway, wherein the signaling pathway inhibitor is an AR pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the AR pathway, and wherein the signaling pathway inhibitor is an HH pathway inhibitor when the determined abnormal operation of the cellular signaling pathway is abnormal operation of the HH pathway;   wherein the abnormal operation of a cellular signaling pathway in the tumor sample from the subject comprises determining activity of the cellular signaling pathway in a tumor sample from the subject based at least on determined expression levels of the three or more target genes of the cellular signaling pathway, wherein determining activity of the cellular signaling pathway comprises determining a level of a transcription factor (TF) element in the tumor sample from the subject, the TF element controlling transcription of the three or more target genes of the cellular signaling pathway, the determining being based at least in part on evaluating a mathematical model relating expression levels of the three or more target genes of the cellular signaling pathway to the level of the TF element, the model being based at least in part on one or more linear combinations of expression levels of the three or more target genes.   
     
     
         20 . The method of  claim 19 , wherein determining activity of the cellular signaling pathway in the sample based at least on the determined expression levels of the three or more target genes of the cellular signaling pathway comprises one or more of:
 determining activity of a Wnt pathway based at least on expression levels of three or more target genes of the Wnt pathway selected from the group comprising: KIAA1199, AXIN2, RNF43, TBX3, TDGF1, SOX9, ASCL2, IL8, SPS, ZNRF3, KLF6, CCND1, DEFA6 and FZD7;   determining activity of an ER pathway based at least on expression levels of three or more target genes of the ER pathway selected from the group comprising: CDH26, SGK3, PGR, GREB1, CA12, XBPI, CELSR2, WISP2, DSCAM, ERBB2, CTSD, TFF1 and NRIP1;   determining activity of an HH pathway based at least on expression levels of three or more target genes of the HH pathway selected from the group comprising: GLI1, PTCH1, PTCH2, IGFBP6, SPP1, CCND2, FST, FOXL1, CFLAR, TSC22D1, RAB34, S100A9, S100A7, MYCN, FOXM1, GLI3, TCEA2, FYN and CTSL1; and   determining activity of an AR pathway based at least on expression levels of three or more target genes of the AR pathway selected from the group comprising: KLK2, PMEPA1, TMPRSS2, NKX3 1, ABCC4, KLK3, FKBPS, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR and EAF2.