Methods for detecting and treating cancers having adenosine pathway activation

Inventors

Willingham, Stephen • Hotson, Andrew • Miller, Richard A.

Assignees

Corvus Pharmaceuticals Inc

Abstract

This disclosure relates to methods for detecting a level of expression of one or more genes 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 in combination with a PD-1 inhibitor and/or a PD-L 1 inhibitor, to treat the cancer. The genes include, without limitation, CD68, CD 163, EBP, 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, SERPINB32, SLC11A1, SLC7A7, SPON1, ST6GALNAC2, TBX21, THBS1, C1R, C1S, C4B3PA, 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, EC SIT, 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 WDR83 OS.

Core Innovation

The invention relates to biomarker-driven treatment of cancer in a subject in need thereof by detecting an increased level of expression of genes or proteins, relative to a control, in a biological sample obtained from the subject. The genes or proteins comprise CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2, and the detected expression pattern is used as a basis for subsequent treatment to thereby treat the cancer.

After the detecting step, the method administers an effective amount of an adenosine 2A receptor antagonist together with an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor. The adenosine 2A receptor antagonist is specified as (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, and specific combinations include using this compound together with nivolumab.

The disclosed embodiments further associate adenosine pathway signaling with transcriptomic/proteomic gene-expression changes, including an adenosine-regulated neutrophil/MDSC and monocyte/macrophage inflammatory gene signature and a reduction of IFNg-related genes in the context of adenosine 2A receptor signaling that is reversed by CPI-444. The document also reports tumor-type correlations for an adenosine-related gene subset and uses these biomarker relationships to support patient selection for an adenosine pathway inhibitor in combination with PD-1/PD-L1 therapy.

Claims Coverage

The consolidated claims coverage includes four inventive features. Across the independent claims, the core inventive structure is the same: detect increased expression of a specified CXCL/IL-1β/PTGS2 gene or protein set relative to a control, then administer an adenosine 2A receptor antagonist together with a PD-1 inhibitor or a PD-L1 inhibitor, with claim-specific selections for agents and indications.

Across the independent claims, the core claimed inventive concept is a method in which detecting increased expression relative to a control of the defined biomarker set CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL-1β, and PTGS2 is linked to subsequent administration of an adenosine 2A receptor antagonist together with PD-1 and/or PD-L1 blockade. Dependent claim language further specifies particular therapeutic agents, including (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, nivolumab, and renal cancer scope.

Stated Advantages

Documented Applications