P3, N=500, Recruiting, Merus N.V. | Not yet recruiting --> Recruiting

P3, N=500, Not yet recruiting, Merus N.V.

Mechanistically, QPH-FR competitively suppressed the formation of the LGR5/RSPO1 complex by binding to LGR5, causing RNF43/ZNRF3 to ubiquitinate the FZD receptor, thereby suppressing the Wnt/β-catenin signaling pathway and exerting stemness inhibition. In summary, the study proposes that a novel peptide QPH-FR from quinoa elucidates the mechanism by which QPH-FR targets LGR5 to enhance chemosensitivity, providing theoretical support for the development of chemotherapeutic adjuvant drugs based on plant peptides.

P3, N=500, Recruiting, Merus N.V. | Not yet recruiting --> Recruiting

P1/2, N=567, Recruiting, Merus N.V. | N=360 --> 567 | Trial completion date: Jun 2025 --> Nov 2027 | Trial primary completion date: Jun 2024 --> Nov 2025

P3, N=500, Not yet recruiting, Merus N.V.

LGR5 expression in LN metastases may influence prognosis. Further analysis may lead to new therapeutic strategies.

P1/2, N=360, Recruiting, Merus N.V. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2024

1 esophageal cancer pt died due to unrelated G5 GI bleeding. Petosemtamab demonstrated promising clinical efficacy among patients with pretreated GEA having EGFR gene amplification and/or overexpression, with a manageable safety profile.

Pts received a median of 2 (range 1-4) lines of prior systemic therapy, including anti-PD-1/PD-L1 in 96% of pts and platinum-based chemotherapy in 92% of pts; 2 pts received prior cetuximab. Petosemtamab demonstrates promising clinical efficacy with a manageable safety profile in pretreated HNSCC pts. Further clinical development in HNSCC is planned with petosemtamab monotherapy and in combination with SOC.

P1/2, N=360, Recruiting, Merus N.V. | Unknown status --> Recruiting | Phase classification: P1 --> P1/2 | N=120 --> 360 | Trial completion date: Jan 2021 --> Jun 2024 | Trial primary completion date: Jan 2021 --> Jun 2023

G9 at 30 days produced the highest yield of cell spheroids, as determined by a sphere forming assay (F=19.147, P<0.001); colony formation assays also exhibited the greatest number of colonies derived from G9 spheroids at 30 days (F=60.767, P<0.01), which also generated the largest mean tumor volume in the subcutaneous tumorigenesis xenograft model (F=12.539, P<0.01). In conclusion, 20 ng/ml EGF + 20 ng/ml bFGF effectively enriched colon CSCs when added to suspension culture for 30 days, and conferred the highest efficiency compared with other combinations.

Furthermore, we found that restoring LGR5 expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing LGR5 gene expression to govern the spheroid formation potential of CRC cells.

In vivo, LGR5-CAR-T cell treatment decreased the tumour burden in mice with OVCAR3 xenografts and a chemotherapy-resistant patient-derived xenograft with high LGR5 expression, compared to CD3+ T cells. In summary, LGR5-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.

Collectively, we elucidate an original regulation of PAR oncogene, a member of cancer stem cells, by RNF43 ubiquitin ligase. It impacts β-catenin signaling and colon cancer growth.

The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.

In line with this, we found no significant correlation between OLFM4 expression, metastasis, and patient survival. In summary, expression of OLFM4 in human CRC seems to be characteristic of differentiation marker expression in CRC but is not a driver of carcinogenesis nor metastatic spread.

Overall, miR-138-5p regulates CRC progression and promotes apoptosis via the SP1/LGR5 axis. This study indicates that miR-138-5p is involved in regulating CRC progression.

These markers might help to identify the cell-lineage identity and analyze the plasticity of each stem cell population. Thus, identification of marker genes for the development of GC and its environment is critical for the clinical application of cancer stem cells in the prevention of stomach cancers.

Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.

Functional analyses using GSCs derived from a murine de novo GBM model induced by oncogenic genes transduction using the Sleeping-Beauty transposon system revealed that expression of Stat5b was induced by culturing under hypoxia together with Lgr5, repressed by Hif2α knockdown, and reduced by Lgr5 knockdown or a Wnt/β-catenin signaling inhibitor ICG-001 treatment...Disruption of Stat5b in an orthotopic transplantation model significantly prolongs event-free survival. These results suggest that Stat5b, regulated by hypoxia and the Wnt pathway, plays an important role in the maintenance and tumorigenicity of GSCs and may be a promising therapeutic molecular target to attack GSCs.

These findings suggest that decreased LGR5 expression in the fat invasion front is associated with more aggressive biological behavior in pancreatic ductal adenocarcinoma, with higher tumor grade, EMT phenotype, and higher vascular invasion.

Based on the PICRUSt-predicted pathways of our GM dataset, we demonstrated that kaempferol downregulated secondary BA synthesis pathways, increased G protein-coupled receptor activity and decreased NOD-like receptor activity, affecting cell differentiation, proliferation, survival, and apoptosis. Collectively, these results reveal that kaempferol effectively attenuates the tumor burden in Apc mice by modulating the BA signaling and GM homeostasis.

Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.

Lastly, ectopic expression of LGR5 attenuated OSR1 over-expression-induced decrease of cell viability and proliferation in acute myeloid leukaemia cells. In conclusion, OSR1 functioned as a tumour suppressor in acute myeloid leukaemia cells by inhibiting LGR5-mediated activation of JNK signalling.

HNK administered by oral gavage at a dose of 5mg/kg bw for 24 weeks demonstrated a significant reduction in the expression of YAP1 and TEAD1 and in the stem marker proteins. Together, these data suggest that HNK prevents colon tumorigenesis in part by inducing PUMA-YAP1 interaction and cytoplasmic sequestration, thereby suppressing the oncogenic YAP1 activity.

Moreover, these phenotypic changes and changes in inflammatory signalling were recoverable after the removal of inflammatory stimuli, suggesting that colon cancer cells have higher plasticity than normal intestinal epithelial cells. In conclusion, our results suggest that sporadic neoplasms in patients with UC are affected by chronic inflammation but are not essentially altered.

These findings support a model in which inactivation of one copy of APC leads to increased numbers of LGR5+ stem cells, many of which are ectopic, in colon crypts of subjects with FAP. Overabundant and ectopic LGR5+ stem cells could lead to an expanded proliferative zone of dividing cells more likely to develop mutations that would contribute to the accelerated adenoma development observed in FAP.

Furthermore, a clear role has emerged for autophagy not only in secretory cells but also in intestinal stem cells, where it affects their metabolism, as well as their proliferative and regenerative capacity. Here, we review the physiological role of autophagy in the context of intestinal epithelial maintenance and how genetic mutations affecting autophagy contribute to the development of intestinal disease.Abbreviations: AKT1S1: AKT1 substrate 1; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; APC: APC regulator of WNT signaling pathway; ATF6: activating transcription factor 6; ATG: autophagy related; atg16l1&lsqb;ΔIEC] mice: mice with a specific deletion of Atg16l1 in intestinal epithelial cells; ATP: adenosine triphosphate; BECN1: beclin 1; bsk/Jnk: basket; CADPR: cyclic ADP ribose; CALCOCO2: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CD: Crohn disease; CDH1/E-cadherin: cadherin 1; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; CGAS: cyclic GMP-AMP synthase; CLDN2: claudin 2; CoPEC: colibactin-producing E. coli; CRC: colorectal cancer; CYP1A1: cytochrome P450 family 1 subfamily A member 1; DC: dendritic cell; DDIT3: DNA damage inducible transcript 3; DEPTOR: DEP domain containing MTOR interacting protein; DSS: dextran sulfate sodium; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2AK4/GCN2: eukaryotic translation initiation factor 2 alpha kinase 4; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel disease; IEC: intestinal epithelial cell; IFN: interferon; IFNG/IFNγ:interferon gamma; IL: interleukin; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LGR5: leucine rich repeat containing G protein-coupled receptor 5; LRRK2: leucine rich repeat kinase 2; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MAPK/JNK: mitogen-activated protein kinase; MAPK14/p38 MAPK: mitogen-activated protein kinase 14; MAPKAP1: MAPK associated protein 1; MAVS: mitochondrial antiviral signaling protein; miRNA: microRNA; MLKL: mixed lineage kinase domain like pseudokinase; MLST8: MTOR associated protein, LST8 homolog; MNV: murine norovirus; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NLRP: NLR family pyrin domain containing; NOD: nucleotide binding oligomerization domain containing; NRBF2: nuclear receptor binding factor 2; OPTN: optineurin; OXPHOS: oxidative phosphorylation; P: phosphorylation; Patj: PATJ crumbs cell polarity complex component; PE: phosphatidyl-ethanolamine; PI3K: phosphoinositide 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PPARG: peroxisome proliferator activated receptor gamma; PRR5: proline rich 5; PRR5L: proline rich 5 like; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RER: rough endoplasmic reticulum; RHEB: Ras homolog, MTORC1 binding; RICTOR: RPTOR independent companion of MTOR complex 2; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; RPTOR: regulatory associated protein of MTOR complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SH3GLB1: SH3 domain containing GRB2 like, endophilin B1; SNP: single-nucleotide polymorphism; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STING1: stimulator of interferon response cGAMP interactor 1; TA: transit-amplifying; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TGM2: transglutaminase 2; TJ: tight junction; TJP1/ZO1: tight junction protein 1; TNBS: 2,4,6-trinitrobenzene sulfonic acid; TNF/TNFα: tumor necrosis factor; Tor: target of rapamycin; TRAF: TNF receptor associated factor; TRIM11: tripartite motif containing 11; TRP53: transformation related protein 53; TSC: TSC complex subunit; Ub: ubiquitin; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; USO1/p115: USO1 vesicle transport factor; UVRAG: UV radiation resistance associated; WIPI: WD repeat domain, phosphoinositide interacting; WNT: WNT family member; XBP1: X-box binding protein 1; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

There was no significant difference in Overall Survival between the PD-L1-positive and PD-L1-negative groups (log-rank test, P = 0.8218). This study showed that PD-L1-positive patients are a unique population with low LGR5 expression, and that LGR5-positive cells may be a promising therapeutic target in PD-L1-negative patients.

This study demonstrated CEACAM6, LGR5 and Wnt pathway suppression by CD151 silencing might occur through TGFβ1 regulation, offering a comprehensive view of CD151's roles in colorectal carcinogenesis. Our findings provide an insight into the CD151-involved signaling network in CRC oncogenesis, which could be utilized to design novel targeted therapies against CD151-based signaling in treatment for CRC.

However, conversely, the expression levels of miR-340 and FOXO1 genes in cisplatin-sensitive cell lines, after 24, 48, and 72 hr of cisplatin treatment, indicated a significant increase (p 0.001) while the expression of LGR5 gene showed a significant decrease in the cisplatin-sensitive cell line (p 0.05). The LGR5, FOXO1, and miR-340 genes can be targeted for early diagnosis and more accurate treatment of ovarian cancer and may prevent some of the ovarian cancer complications such as infertility.

Our study unravels a tumor-promoting role for LGR5 through activation of canonical Wnt/β-catenin signaling in the hepatoblast-like HCCs. In conclusion, our results suggest that LGR5/R-Spo1/Wnt3a generates an axis that mediates the acquisition of aggressive phenotype specifically in hepatoblast-like subset of HCCs and might represent a valuable target for treatment of HCC tumors with aberrant activation of Wnt/β-catenin pathway.

These findings suggest that the wider spectrum of tumor morphology in CAC may be associated with absence of a LGR5-expressing intestinal stem cell phenotype.

Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.

Our results reveal the relationship between LGR5 expression and MMR protein profiles in PD-CRC. A further study is warranted to confirm these findings.

Furthermore, compound K synergistically potentiated antitumor effect of 5-fluorouracil (5-FU) or Doxorubicin to reduce the survival genes and cytotoxicity in HCT116 cells. Overall, our findings provide scientific insight that compound K induces apoptosis in colon cancer cells via caspase and p53 dependent LGR5 inhibition with combination therapy potential with 5-FU or doxorubicin.

Conclusion The expressions of ABCG2 and SOX2 in colorectal cancer tissues were associated with patients’ prognosis. Especially, SOX2 can be a potential predictive marker for patients with colorectal cancer.

Conclusion The expressions of ABCG2 and SOX2 in colorectal cancer tissues were associated with patients’ prognosis. Especially, SOX2 can be a potential predictive marker for patients with colorectal cancer.

Conclusion The expressions of ABCG2 and SOX2 in colorectal cancer tissues were associated with patients’ prognosis. Especially, SOX2 can be a potential predictive marker for patients with colorectal cancer.

Tumoral CD44v expression might be a useful prognostic marker for patients after curative resection of NSCLC.