Assessment of the p13k cellular signaling pathway activity using mathematical modelling of target gene expression

Abstract

The present invention relates to a method comprising inferring activity of a PI3K cellular signaling pathway in a tissue and/or cells and/or a body fluid of a medical subject based at least on expression levels of one or more target gene(s) of the PI3K cellular signaling pathway measured in an extracted sample of the tissue and/or the cells and/or the body fluid of the medical subject. The present invention further relates to an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising program code means for causing a digital processing device to perform such a method.

1 . A kit for determining abnormal activity of a PI3K cellular signaling pathway in a subject, comprising:
 one or more components for determining expression levels of three or more target genes of the PI3K cellular signaling pathway in a sample of the subject, wherein the one or more components are primers and probes for detecting the expression levels of the three or more target genes, and wherein the three or more target genes are selected from the group consisting of: AGRP, BCL2L11, BCL6, BNIP3, BTG1, CAT, CAV1, CCND1, CCND2, CCNG2, CDKN1A, CDKN1B, ESR1, FASLG, FBXO32, GADD45A, INSR, MXI1, NOS3, PCK1, POMC, PPARGC1A, PRDX3, RBL2, SOD2 and TNFSF10; and   a digital processing device configured to determine the abnormal activity of the PI3K cellular signaling pathway in the subject, wherein the inferring comprises:
 determining a level of a FOXO transcription factor (TF) element in the sample, the FOXO TF element controlling transcription of the three or more target genes of the PI3K 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 PI3K cellular signaling pathway to the level of the FOXO TF element; 
 inferring the activity of the PI3K cellular signaling pathway subject based on the determined level of the FOXO TF element in the sample; and 
 determining that the PI3K cellular signaling pathway is operating abnormally in the subject based on the inferred activity of the PI3K cellular signaling pathway in the sample. 
   
     
     
         2 . The kit according to  claim 1 , further comprising primers and probes for detecting the expression levels of an additional target gene selected from the group consisting of: ATP8A1, C10orf10, CBLB, DDB1, DYRK2, ERBB3, EREG, EXT1, FGFR2, IGF1R, IGFBP1, IGFBP3, LGMN, PPM1D, SEMA3C, SEPP1, SESN1, SLC5A3, SMAD4 and TLE4. 
     
     
         3 . The kit according to  claim 1 , further comprising primers and probes for detecting the expression levels of an additional target gene selected from the group consisting of: ATG14, BIRC5, IGFBP1, KLF2, KLF4, MYOD1, PDK4, RAG1, RAG2, SESN1, SIRT1, STK11 and TXNIP. 
     
     
         4 . The kit according to  claim 1 , wherein the kit comprises primers and probes for determining the expression levels of at least nine target genes selected from the group consisting of: AGRP, BCL2L11, BCL6, BNIP3, BTG1, CAT, CAV1, CCND1, CCND2, CCNG2, CDKN1A, CDKN1B, ESR1, FASLG, FBXO32, GADD45A, INSR, MXI1, NOS3, PCK1, POMC, PPARGC1A, PRDX3, RBL2, SOD2 and TNFSF10. 
     
     
         5 . The kit according to  claim 4 , further comprising primers and probes for detecting the expression levels of an additional target gene selected from the group consisting of: ATP8A1, C10orf10, CBLB, DDB1, DYRK2, ERBB3, EREG, EXT1, FGFR2, IGF1R, IGFBP1, IGFBP3, LGMN, PPM1D, SEMA3C, SEPP1, SESN1, SLC5A3, SMAD4 and TLE4. 
     
     
         6 . The kit according to  claim 4 , further comprising primers and probes for detecting the expression levels of an additional target gene selected from the group consisting of: ATG14, BIRC5, IGFBP1, KLF2, KLF4, MYOD1, PDK4, RAG1, RAG2, SESN1, SIRT1, STK11 and TXNIP. 
     
     
         7 . The kit according to  claim 1 , wherein the kit comprises primers and probes for determining the expression levels of all target genes selected from the group consisting of: AGRP, BCL2L11, BCL6, BNIP3, BTG1, CAT, CAV1, CCND1, CCND2, CCNG2, CDKN1A, CDKN1B, ESR1, FASLG, FBXO32, GADD45A, INSR, MXI1, NOS3, PCK1, POMC, PPARGC1A, PRDX3, RBL2, SOD2 and TNFSF10. 
     
     
         8 . The kit according to  claim 1 , wherein the kit is for determining the abnormal activity of the PI3K cellular signaling pathway in an extracted sample of a tissue and/or cells and/or body fluid of the subject. 
     
     
         9 . The kit according to  claim 1 , wherein determining further comprises:
 recommending prescribing a drug for the subject that corrects for the determined abnormal operation of the PI3K cellular signaling pathway.   
     
     
         10 . The kit according to  claim 1 , wherein determining further comprises one or more of:
 diagnosis based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   prognosis based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   drug prescription based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   prediction of drug efficacy based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   prediction of adverse effects based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   monitoring of drug efficacy;   drug development;   assay development;   pathway research;   cancer staging;   enrollment of the medical subject in a clinical trial based on the inferred activity of the PI3K cellular signaling pathway in the tissue and/or the cells and/or the body fluid of the medical subject;   selection of subsequent test to be performed; and   selection of companion diagnostics tests.   
     
     
         11 . The kit according to  claim 1 , wherein the determined abnormal operation of the PI3K cellular signaling pathway is overactive 
     
     
         12 . The kit according to  claim 11 , wherein determining further comprises recommending prescribing a specific treatment for the subject that inhibits or deregulates the activity of the PI3K cellular signaling pathway. 
     
     
         13 . The kit according to  claim 11 , wherein determining further comprises providing, based on the determined abnormal operation of the PI3K cellular signaling pathway, a recommendation for medical intervention configured to inhibit or deregulate the activity of the PI3K cellular signaling pathway. 
     
     
         14 . The kit according to  claim 13 , wherein the recommendation for medical intervention configured to inhibit or deregulate the activity of the PI3K cellular signaling pathway comprises recommending or selecting a drug that inhibits or downregulates the activity of the PI3K cellular signaling pathway. 
     
     
         15 . The kit according to  claim 1 , further comprising a non-transitory storage medium storing instructions that are executable by the digital processing device to determine the abnormal activity of the PI3K cellular signaling pathway in the subject. 
     
     
         16 . The kit according to  claim 1 , further comprising a computer program comprising program code means for causing the digital processing device to determine the abnormal activity of the PI3K cellular signaling pathway in the subject.