Determination of JAK-STAT3 pathway activity using unique combination of target genes
A bioinformatics process which provides an improved means to detect a JAK-STAT3 cellular signaling pathway in a subject, such as a human, based on the expression levels of at least three unique target genes of the JAK-STAT3 cellular signaling pathway measured in a sample. The invention includes 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. Kits are also provided for measuring expression levels of unique sets of JAK-STAT3 cellular signaling pathway target genes.
1. A method of treating a subject suffering from a disease associated with an activated JAK- STAT3 cellular signaling pathway, comprising:
receiving data on expression levels of at least six target genes derived from a sample obtained from the subject, wherein a JAK-STAT3 transcription factor element controls transcription of the at least six target genes, and wherein the at least six target genes are selected from BCL2L1, BIRC5, CCND1, CD274, FOS, HIF1A, HSP90AA1, HSP90AB1, MMP1, and MYC, or from BCL2L1, CD274, FOS, HSP90B1, HSPA1B, ICAM1, IFNG, JunB, PTGS2, STAT1, TNFRSF1B, and ZEB1;
calculating an activity level of the JAK-STAT3 transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the calibrated pathway model which define an activity level of JAK-STAT3 transcription factor element;
calculating an activity level of the JAK-STAT3 cellular signaling pathway in the sample based on the calculated activity level of the JAK-STAT3 transcription factor element in the sample, wherein the calculated activity level of the JAK-STAT3 cellular signaling pathway indicates that the JAK-STAT3 cellular signaling pathway in the sample is active, wherein the calculated activity level of the JAK-STAT3 cellular signaling pathway indicates that the JAK-STAT3 cellular signaling pathway in the sample is active when the calculated activity level of the JAK-STAT3 cellular signaling pathway is above a log-odds ratio of 1:1; and,
administering to the subject a JAK-STAT3 inhibitor in response to receiving the indication that the activity level of the JAK-STAT3 cellular signaling pathway is active.
2. The method of claim 1 , wherein the at least six target genes comprise at least six target genes selected from BCL2L1, BIRC5, CCND1, CD274, FOS, HIF1A, HSP90AA1, HSP90AB1, MMP1, and MYC, or from BCL2L1, CD274, FOS, HSP90B1, HSPA1B, ICAM1, IFNG, JunB, PTGS2, STAT1, TNFRSF1B, and ZEB1.
3. The method of claim 1 , wherein the at least six target genes selected from BCL2L1, BIRC5, CCND1, CD274, FOS, HIF1A, HSP90AA1, HSP90AB1, MMP1, and MYC, are selected based on their ability to differentiate between solid tumor, preferably epithelial samples of which the activity of the JAK-STAT3 cellular signaling pathway is active vs. inactive and/or are used in a calibrated pathway model which is calibrated on solid tumor, preferably lung samples, or wherein the at least six target genes selected from BCL2L1, CD274, FOS, HSP90B1, HSPA1B, ICAM1, IFNG, JunB, PTGS2, STAT1, TNFRSF1B, and ZEB1, are selected based on their ability to differentiate between hematological samples of which the activity of the JAK-STAT3 cellular signaling pathway is active vs. inactive and/or are used in a calibrated pathway model which is calibrated on hematological samples.
4. The method of claim 1 , wherein the JAK-STAT3 inhibitor is STA-21, LLL-3, curcumin, or AZD9150.
5. The method of claim 1 , wherein the disease is a cancer or an immune disorder.