Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy. SIGNIFICANCE: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.
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PMID:An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response. 3139 8

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Chemotherapy is one of the main treatments for cancer, but the antitumor effect of chemotherapeutic drugs is affected by the patient's immune status. The programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis is an important central checkpoint in tumor progression. The present study demonstrated a significant synergistic effect of PD-1 inhibitor and oxaliplatin, cisplatin, etoposide, cytarabine, ifosfamide and carboplatin. There was no difference in cytotoxicity between the groups with or without PD-L1 inhibitor. It was also observed that cytotoxicity of T cells combined with PD-1 inhibitor against DLBCL cells was inhibited by dexamethasone addition to the culture system at 24, 48 and 72 h. There was no difference in cytotoxicity between the group of dexamethasone added at 96 h and the group without dexamethasone at 96 h. Then, we selected a PD-1 inhibitor combined with a chemotherapeutic regimen in a Pfeiffer cell mouse xenograft model. At 21 days, the reduction in tumor size was more obvious in the DHAP combined with PD-1 inhibitor group (dexamethasone after 96 h of PD-1) compared with that in the DHAP (P=0.007), the PD-1 inhibitor (P=0.001) and the DHAP combined with PD-1 inhibitor (dexamethasone after 24 h of PD-1) (P=0.005) groups. However, the reduction in tumor size was more obvious in the GemOx combined with PD-1 inhibitor group compared with that in the GemOx group (P=0.037). Therefore, the present study demonstrated the synergistic effects of PD-1 inhibitor combined with chemotherapeutic regimens in DLBCL.
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PMID:Synergistic effect of programmed death-1 inhibitor and programmed death-1 ligand-1 inhibitor combined with chemotherapeutic drugs on DLBCL cell lines in vitro and in vivo. 3304 18