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Methods for detecting and treating cancers having adenosine pathway activation

A technology for cancer, adenosine, in the field of detection and treatment of cancers with adenosine pathway activation

Inactive Publication Date: 2021-04-13
CORVUS PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Measurement of adenosine levels in tumors is technically challenging due to the molecule's half-life of less than ten seconds

Method used

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  • Methods for detecting and treating cancers having adenosine pathway activation
  • Methods for detecting and treating cancers having adenosine pathway activation
  • Methods for detecting and treating cancers having adenosine pathway activation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0195] Example 1: mRNA expression in PBMC is regulated by NECA

[0196]Peripheral cells from normal healthy humans treated with 5'-N-ethylcarboxamidoadenosine (NECA) and activated with anti-CD3 / CD28 antibodies were analyzed by NanoString hybridization-based quantification (NanoString Technologies, Inc.). Purified RNA from blood mononuclear cells (PBMC). figure 1 NanoString quantitative data are shown; marked genes were consistently regulated by NECA treatment. Each point represents the expression level of a specific gene. Dot shading indicates the concentration of NECA and / or different PBMC donors used. Genes above the diagonal axis are upregulated relative to DMSO control. Genes below the diagonal axis are downregulated relative to DMSO control. Table 3 provides a list of genes up- or down-regulated by 0.1 μM, 1 μM and / or 10 μM NECA treatment (compared to vehicle-treated controls) as determined by NanoString NPR1 sequencing.

[0197] Table 3. NanoString NECA Response

...

example 2

[0209] Example 2: CPI-444 inhibits NECA-induced cytokine expression

[0210] Activation of CXCL5 protein expression by NECA was assessed. PBMCs were collected from two different human donors. Such as Figure 2A As indicated, cells were treated with NECA followed by CPI-444 and then anti-CD3 / CD28 to activate PBMCs. CPI-444 (Corvus Pharmaceuticals) is an antagonist of the adenosine A2A receptor. Two days after activation, culture supernatants were assessed for CXCL5 protein by ELISA. exist Figure 2B and 2C The data is provided in . Activation of CXCL5 expression by NECA. This activation in CXCL5 could be blocked by the addition of CPI-444, an A2AR receptor antagonist that neutralizes the immunosuppressive effect of NECA. This demonstrates that induction of CXCL5 is specific for signaling through adenosine receptors.

example 3

[0211] Example 3: CCL20 expression correlates with expression of a subset of adenosine-regulated genes in multiple tumor types

[0212] Using the Cancer Genome Atlas (National Cancer Institute, National Human Genome Research Institute); available at Genomic Data Commons Data Portal cancergenome. nih.gov)), the gene expression of CCL20 compared to the expression of a subset of genes exhibiting regulation by adenosine was determined in various solid tumor types. For each tumor type, the expression level of the adenosine pathway was calculated as the mean of Log2 showing the expression of the genes induced by adenosine (CXCL1, CXCL2, CXCL3, CXCL5, SERPINB2, IL8 and IL1B). Gene expression of CCL20 is highly correlated with expression of this subset of genes in solid tumors ( Figure 3A and 3B ), thus suggesting that CCL20 (and co-regulated genes) can be used as a surrogate for the expression of this subset of genes. p<0.0001 for all tumor types. This group of genes represented...

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Abstract

The present disclosure relates to methods for detecting expression levels of one or more genes in a subject having or suspected of having a cancer and optionally treating the subject with an adenosine pathway antagonist (e.g., an adenosine A2A receptor (ADORA2A) antagonist) in combination with a PD-1 inhibitor and / or a PD-L1 inhibitor to treat the cancer. The genes comprise, but are not limited to, CD68, CD163, LBP, CCL2, CCL3,CCL7,CCL24,CCNE1,CD14,CD300E,CD86,CD93,CLEC5A, CSF3,CXCL1,CXCL2,CXCL3,CXCL5,CXCL6,CXCL8,DFNA5,ECEL1,EPB41L3,EHF,FUT7,GALM,GBP6,GPR157,HAS1,IL1A,IL-1beta,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,ITGAM,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,CD164,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 WDR83OS.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from: U.S. Provisional Patent Application No. 62 / 697,303, filed July 12, 2018; U.S. Provisional Patent Application No. 62 / 742,919, filed October 8, 2018; U.S. Provisional Patent Application No. 62 / 757,630, filed November 8; and U.S. Provisional Patent Application No. 62 / 846,525, filed May 10, 2019; each of said U.S. Provisional Patent Applications Both are incorporated herein by reference in their entirety. Background technique [0003] Adenosine is a signaling molecule used by the body to limit inflammation and immune responses. Many different types of tumors generate and actively maintain large amounts of adenosine within the tumor microenvironment. One of the ways tumor cells produce adenosine is by expressing large amounts of an enzyme called CD73 on their surface. CD73 generates adenosine, and this helps maintain high levels of adenosine in the tumor microenvironment. [0004] A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K45/00A61P35/00C07K14/705C07K16/28C07K16/30G01N33/574
CPCA61P35/00C07K14/705C07K16/2809C07K16/2818C07K16/2827A61K2039/505C07K14/47A61K45/06A61K31/519G01N2800/52G01N33/57492G01N33/6869C12Q1/6886C12Q2600/158C12Q2600/106A61K2300/00G01N33/57484G01N2800/7028G01N2333/70592C07K16/2896G01N2333/521G01N2333/70596
Inventor S·威林厄姆A·霍特森R·A·米勒
Owner CORVUS PHARMACEUTICALS INC
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