Methods for detecting and treating cancers having adenosine pathway activation
Inventors
Willingham, Stephen • Hotson, Andrew • Miller, Richard A.
Assignees
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Publication Number
US-12174192-B2
Publication Date
2024-12-24
Expiration Date
Abstract
This disclosure relates to methods for detecting a level of expression of one or more genes (or proteins) in a subject having or suspected of having cancer, and optionally treating the subject with an adenosine pathway antagonist, for example an adenosine A2A receptor (ADORA2A) antagonist, to treat the cancer. The genes (or proteins) include, without limitation, CD68, CD163, LBP, CCL2, CCL3, CCL7, CCL24, CCNE1, CD 14, CD300E, CD86, CD93, CLEC5A, CSF3, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, DFNA5, ECEL1, EPB41L3, EHF, FUT7, GALM, GBP6, GPR157, HAS1, IL1A, IE-1β, IL23, IL24, IL5, IL6, IL8, INHBA, LAP3, LAYN, LOC100505585, MRPL11, NID1, OST4, PADI2, PID1, PLAUR, PPBP, PTGS2, RHCG, SERPINB2, SLC11A1, SLC7A7, SPON1, ST6GALNAC2, TBX21, THBS1, C1R, C1S, C4BPA, CCL11, CCL20, CXCL16, CXCL2, HAMP, HSD11B1, IT GAM, LIF, SAA1, TFRC, TLR5, TNFSF14, TREM2, APP, ATG10, BCL2, CCL15, CD24, CD46, CD59, CREB5, CX3CL1, CXCL14, CYFIP2, DEFB1, DPP4, ECSIT, EPCAM, IFIT1, IGF1R, ITGA6, ITGB3, MAP2K4, MAPK1, MASP1, PPARG, RORC, SPA17, STAT5B, TOLLIP, AKT3, BMI1, CD 164, CD34, CDH5, CREB1, DOCK9, ENG, HMGB1, ITGA1, JAM3, MAF, MAPK3, MAPK8, MCAM, MFGE8, NOTCH1, NRP1, PRKCE, SMAD2, TAL1, THY1, TNFSF12, TRAF6, TXNIP, VEGFA, S100A8, and/or WDR830S.
Core Innovation
The invention provides a method of treating a subject having cancer by obtaining a biological sample from the subject and detecting an increased level of expression of genes or proteins in the biological sample relative to a control. The genes or proteins comprise CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2, and this increased expression is used in connection with treating the cancer.
The method further comprises administering to the subject an effective amount of an adenosine pathway inhibitor to thereby treat the cancer, where the adenosine pathway inhibitor is characterized as an adenosine 2A receptor antagonist. In specific embodiments, the adenosine 2A receptor antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.
The disclosed framework includes correlation analyses across tumor types and renal cell carcinoma trial baseline samples linking CCL20 and related AdenoSig genes to the adenosine-regulated signature. The document reports clinical associations between high baseline AdenoSig and tumor regression with CPI-444 therapy, including surrogate biomarkers such as CCL20/CX3CL1 and CD68/CD163.
Claims Coverage
The consolidated content includes two independent claims with a shared core inventive concept: detect increased expression of a defined gene/protein set relative to a control in a biological sample, then administer an adenosine pathway inhibitor. Across the independent claims, the inventive features comprise a biomarker-based detection step and subsequent administration of an adenosine pathway inhibitor, with renal cancer and a specific inhibitor compound recited for the renal cancer claim.
Biomarker-guided administration for treating cancer
Obtaining a biological sample from the subject, detecting an increased level of expression of genes or proteins relative to a control, wherein the genes or proteins comprise CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2, and administering to the subject an effective amount of an adenosine pathway inhibitor thereby treating the cancer.
Renal cancer treatment using specified biomarker set and specified ADORA2A antagonist
Obtaining a biological sample from the subject, detecting an increased level of expression relative to a control wherein the genes or proteins comprise CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2, and administering to the subject an effective amount of (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine thereby treating the renal cancer.
Across the independent claims, treatment is guided by detecting increased expression relative to a control of the specified CXCL1/CXCL2/CXCL3/CXCL5/CXCL6/CXCL8/IL-1β/PTGS2 gene or protein panel in a biological sample, followed by administration of an adenosine pathway inhibitor, with renal cancer specifically treated using a defined ADORA2A antagonist.
Stated Advantages
Select cancer patients and guide treatment with an adenosine pathway inhibitor using biomarker-expression based strategies.
Indicate susceptibility or candidacy for adenosine-pathway inhibition based on increased or correlated gene/protein expression relative to a control.
Not explicitly described in patent.
Documented Applications
Treating cancer by obtaining a biological sample, detecting increased expression of CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2 relative to a control, and administering an adenosine pathway inhibitor.
Treating renal cancer by obtaining a biological sample, detecting increased expression of CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2 relative to a control, and administering (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.
Not explicitly described in patent.
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