NT5E overexpression

Therefore, we sought to evaluated different treatment approaches in BC cells (Dapagliflozin, a SGLT2 inhibitor; Paclitaxel, the standard chemotherapy for BC; and ARL67156/APCP, inhibitors of CD39 and CD73, respectively). Indeed, the overexpression of the NT5E gene in patients with ER + tumors is strongly associated with reduced overall survival and progression-free interval. However, more studies are needed to fully understand the interactions and mechanism underlying these co-treatment multi-targeting approaches.

In contrast, CD73 overexpression dramatically reduced the in vivo anticancer activity of Bortezomib in immunocompetent mice, with tumor growth inhibition rates from 52.18 % for LLC/vector down to 8.75 % for LLC/NT5E homografts. These findings give new insights into the anticancer mechanisms of proteasome inhibitors.

BsAb CD73xEGFR outperforms oleclumab as it inhibits the CD73/ADO immune checkpoint in an EGFR-directed manner and concurrently counteracts several oncogenic activities of EGFR and CD73. Therefore, bsAb CD73xEGFR may be of significant clinical potential for various forms of difficult-to-treat solid cancer types.

High infiltration of anti-tumor immune cells in both tumors and margins results in good prognosis, while in patients with minimal infiltration in tumors in spite of high infiltration in margins results in poor prognosis. Targeted CD73 immune-checkpoint inhibition may improve clinical outcome.

Our results show a novel function of CD73 regulates hepatocytes pyroptosis and highlights the therapeutic opportunity for reducing the disease process in ALD.

In sum, CD73 is an effector of EGF/EGFR-mediated local invasion and a potential therapeutic target and candidate predictive marker for advanced HPV-negative HNSCC.

Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8 T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.

NT5E could serve as a potential prognostic biomarker for cancers. The potential mechanism may be related to the upregulated EMT function of CAFs, which provides novel inspiration for immunotherapy by targeting CAFs with high NT5E expression.

These findings suggested that CD73 might promote the growth of ccRCC and contribute to poor prognosis. Taken together, CD73 may be a potential therapeutic target in ccRCC.

This study, together with our previous reports, confirms that CD73 inhibition can reduce adenosine generation, overcome immune suppression, and restore lysis of MM cells. Based on these results, ORIC-533 is being studied as a single agent in a Phase 1 clinical trial in patients with relapsed or refractory multiple myeloma.

The findings indicated the CD73/EZH2 factors inhibition by SPION-TMC-FA NPs as a promising therapeutic strategy in breast cancer treatment.

Predominantly expressed on CAFs, the upregulation of NT5E might predict an immunosuppressive TME for HNSC patients who may benefit little from immunotherapy. Targeting CAFs with high NT5E expression might be a novel therapeutic strategy for HNSC patients.

As expected, knockdown of CD73 inhibited the MAPK signaling pathway, and the suppressive effect of CD73 knockdown on proliferation, migration, invasion and invadopolia formation was reversed by a MAPK signaling activator. Our results suggest that CD73 could promote the proliferation, migration, invasion and invadopodia formation of HNSCC via the MAPK signaling pathway and provide new mechanistic insights into the nonimmunological role of CD73 in HNSCC.

This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73 tumors and enhancing intratumoral activation.

Higher CD73 expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. Mechanistically, CD73 is regulated by ERK-Jun pathway, wherein c-Jun regulates CD73 expression via binding to CD73 genomic regions.

In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.

Noteworthy, we observed higher CD38 expression on WBC than blasts in MRD > 0.1% patients. We suggest that NT5E gene and CD38 protein expression, of the ectonucleotidases family, could provide interesting prognostic biomarkers for childhood B-ALL.

PDAC and AC shared CD73 Overexpression while A2AR was overexpressed in PDAC only. In PDAC, CD73 and A2AR showed an opposed  prognostic effect but both had no prognostic impact on AC. In addition, tumor immune response showed a controversial impact on the prognosis of PDAC and AC.

We performed a detailed bioinformatics analysis of NT5E in HNSCC, and the results showed that the overexpression of NT5E in HNSCC was associated with poor prognosis. Our further investigation of the coexpression pattern of HNSCC could provide a reference for drug resistance and immunotherapy studies.

Recent clinical proof of concept data demonstrated a significant improvement in progression free survival for non-small cell lung cancer patients upon targeting CD73 with the oleclumab anti-CD73 antibody in combination with anti-PDL1, relative to anti-PDL1 checkpoint inhibitor treatment alone.We developed ORIC-533, a potent, orally bioavailable, AMP-competitive, small molecule inhibitor of CD73, that is highly selective for CD73 and exhibits picomolar potency in biochemical assays, completely blocking adenosine production from AMP. Taken together, these results demonstrate that the ORIC CD73 inhibitor potently inhibits the adenosine pathway, which restores anti-tumor immunity and therefore holds potential for patients with MM. Based upon these data, ORIC-533 is being studied as a single agent in a Phase 1 clinical trial in patients with relapsed or refractory multiple myeloma.

CD73 play an important role in LUAD cells proliferation and migration. These data allowed to support CD73 as a therapeutic target for LUAD.

High CD73 expression indicated an immunoevasive contexture with CD8+ T cell dysfunction and represented an independent predictor for adverse clinical outcomes. As a potential immunotherapeutic target, CD73 could potentially be a novel biomarker for adjuvant chemotherapy, targeted therapies and immunotherapy. The crucial role of CD73 in the therapeutic landscape of GC needs further validation retrospectively and prospectively.

Overexpressing CD73 in CHLA-20 and CHLA-90 cells with low CD73 and silencing in CHLA-171 and CHLA-172 cells with high CD73 showed that CD73 regulates epithelial to mesenchymal transition (E-Cadherin, N-Cadherin, Vimentin), stemness maintenance (Sox2, Nanog, Oct3/4), self-renewal capacity (Notch), and differentiation inhibition (leukemia inhibitory factor, LIF) proteins (confocal-immunofluorescence). These results demonstrate that high CD73 can predict good prognosis in NB, and further suggest that CD73 regulates stemness maintenance in cells that defy clinical therapy.

This study therefore demonstrates that: 1. CD73-mediated adenosine activity suppresses the cytolytic activity of T-cells against tumor cells in the MM BM milieu; and 2. CD73 inhibition can overcome immune suppression and restore lysis of MM cells by autologous T-cells.

By the subcutaneous xenograft model, we confirmed the promotive roles of CD73 in regulating cell proliferation and glycolysis in gastric cancer. This study provides strong evidence of the involvement of CD73 in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

In addition, we selected another cohort consisting of 38 ESCC patients receiving nivolumab or pembrolizumab and found that treatment response and survival benefit to immunotherapy were strongly correlated with the expression levels of CD73/programmed death ligand 1. The findings of our study indicate CD73 may be an independent prognostic factor for ESCC patients who underwent esophagectomy. Furthermore, it may be associated with the patient responses to immunotherapy.

These results were corroborated by NT5E mRNA profiling. Papillary carcinomas feature enhanced CD73 protein and mRNA expression with distinct and intense staining, more pronounced in the invasive fronts of the tumors.

Notably, the overexpression of CD73 or low tumour-infiltrating CD8 T cells was an independent indicator for predicting the OS and DFS of ICC patients. We revealed that CD73 expression and low tumour-infiltrating CD8T cells are valuable predictors of survival and recurrence in patients with ICC.

Furthermore, circ_ASAP2 modulated cell DDP sensitivity and functional behaviors by targeting miR-330-3p. Knockdown of circ_ASAP2 promoted DDP sensitivity and suppressed malignant behaviors of DDP-resistant gastric cancer cells through targeting the miR-330-3p/NT5E axis.

CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4, CD8 and CD21 TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.

The aim of this study was to evaluate the effect of the NSAIDs, naproxen, piroxicam, meloxicam, ibuprofen, sodium diclofenac, acetylsalicylic acid, nimesulide, and ketoprofen on CD73 expression in GBM and mononuclear cells...For analysis of the mechanism of action of MTX, GBM cells were treated with APCP (CD73 inhibitor), dipyridamole (inhibitor of adenosine uptake), ABT-702 (adenosine kinase enzyme inhibitor), or caffeine (P1 adenosine receptor antagonist), before treatment with MTX and AMP, in the presence or not of mononuclear cells. In summary, only MTX increased the expression of CD73 in GBM cells decreasing cells viability by mechanisms independent of the adenosinergic system. Further studies are needed to understand the role of MTX in the GBM microenvironment.

Furthermore, in PD-1/PD-L1/CD73 triple KI humanized mice implanted with MC38 tumors, combined CD73 and PD-1/PD-L1 blockade showed greater tumor inhibition than monotherapies. Taken together, CD73 humanized mice and their variants are useful tools for in vivo efficacy evaluation of candidate human CD73 antibodies and combination therapies being considered for clinical trials.

Taken together, these preclinical results indicate the CD73 inhibitor ORIC-533 has best-in-class properties in reversing immunosuppression in tumors. ORIC-533 is currently undergoing GLP studies to support an IND filing in the first half of 2021.

In vitro one-way mixed lymphocyte reaction results demonstrate the utility of combining CD73 inhibition with PD-1 blockade, as Sym024 acts to reverse the immune suppressive effect of adenosine production, thereby allowing effective T cell activation by an anti-PD-1 antibody (Sym021). Dose-proportional and linear pharmacokinetics (PK) was observed at high dose levels while nonlinear PK became evident at lower exposure levels. Sym024 is currently under clinical investigation.