Our prognostic signature effectively predicts LSCC prognosis, with MMP3 identified as a potential novel biomarker for LSCC treatment. Furthermore, our findings underscore the critical role of immune-based therapies in improving outcomes, especially for low-risk patients.

We first demonstrated that hsa_circ_0125356 was significantly upregulated and served as a biomarker for gemcitabine resistance in NSCLC by sponging miR-582-5p/FGF9 axis to regulate the WNT canonical and non-canonical signaling pathways, which provided a new direction for identification of therapeutic targets for the treatment of gemcitabine resistance of NSCLC.

Combining tegavivint with PARP-1/2 inhibitor talazoparib results in synergistic MCL cell death in vitro, and in vivo this combination significantly prolonging the survival of an MCL PDX. Together, our results define the role of TBL1X in maintaining genomic stability in MCL and establish targeting TBL1X as a novel therapeutic strategy for patients with this incurable disease.

The addition of the Wnt activator LiCl reversed DK419-induced effects on β-catenin nuclear translocation and Cyclin D1 and MGMT expression. For the first time, our findings demonstrate that DK419 can significantly enhance glioblastoma sensitivity to TMZ by modulating the Wnt/β-catenin pathway to downregulate MGMT expression.

P1, N=9, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

This identified TNIK, which is modulated by NCB-0846, as a novel target for platinum-resistant HGSC...Our findings identified the TNIK-CDK9 axis as druggable targets mediating platinum resistance and cell viability in HGSC. With AI at the forefront of drug discovery, this work highlights how to ensure that AI findings are biologically relevant by combining compound screens with physiologically relevant models thus supporting the identification and validation of potential drug targets.

Indoxyl sulfate activated the Akt/β-Catenin/c-Myc pathway as evidenced by the Akt inhibitor MK2206, which decreased both β-Catenin and c-Myc protein levels, and the β-Catenin inhibitor XAV-939, which reduced c-Myc protein levels. These findings indicate that the elevation of indoxyl sulfate levels in the blood, due to CKD progression, could worsen CRC by promoting the proliferation of CRC cells and enhancing EGF signaling. Therefore, indoxyl sulfate could potentially serve as a therapeutic target for CRC aggravation in patients with CKD.

P1, N=70, Active, not recruiting, Eisai Co., Ltd. | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

LGALS4 overexpression inhibited CRC cell growth, induced cell cycle arrest and enhanced 5-fluorouracil (5-FU)-induced apoptosis...The downregulatory effect of LGALS4 on glycolysis-related genes was further enhanced by the addition of the β-catenin inhibitor XAV-939...Overexpression of LGALS4 reduced the proliferation and glycolytic capacity of CRC cells and also enhanced their sensitivity to 5-FU. These results may potentially provide new perspectives for CRC treatment and targets for future clinical intervention strategies.

P1, N=24, Recruiting, Ohio State University Comprehensive Cancer Center | N=18 --> 24 | Trial completion date: Dec 2024 --> Jul 2029 | Trial primary completion date: Dec 2024 --> Jul 2025

P1, N=24, Recruiting, Ohio State University Comprehensive Cancer Center | N=18 --> 24 | Trial completion date: Dec 2024 --> Jul 2029 | Trial primary completion date: Dec 2024 --> Jul 2025

Notably, Wnt/β-catenin activation with LiCl significantly enhanced the proliferation and epithelial-mesenchymal transformation (EMT) inhibition effect of silencing FNDC1, whereas Wnt/β-catenin inhibition with XAV-939 significantly weakened the proliferation and EMT promotion effect of FNDC1...These data suggested that FNDC1 exerts its oncogene function through modulating Wnt/β-catenin signaling pathway. In conclusion, FNDC1 promotes cell proliferation, migration, invasion, and EMT through modulating Wnt/β-catenin signaling pathway in breast cancer, providing a new idea for the development of breast cancer therapeutic targets.

The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial.

Activation of the Wnt/β-catenin pathway mediates the high expression of PD-L1 to promote the resistance of NSCLC cells to icotinib. Thus, targeted inhibition of PD-L1 expression is of benefit for the treatment of NSCLC.

Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small-molecule inhibitors and reveals a potential therapeutic target for CRC.

Pharmacologic interactions between EB and the Wnt signaling inhibitors IGC-011 and PRI-724 were determined by the combination index method and showed antagonism, indicating that EB acts on the same pathway as these inhibitors...Following exposure to human liver microsomes, EB was metabolized by NADPH-dependent oxidation and UDPG-dependent glucuronidation, as evidenced by the elimination of EB cytotoxicity against SCLC cells. Taken together, these data indicate that EB, a steroid hormone in plants consumed in the human diet, is pharmacologically active in drug-sensitive and drug-resistant SCLC cells in the Wnt signaling pathway, alters apoptotic gene expression, and is a substrate for microsomal modifications.

The Wnt inhibitor ICG-001 and PKM activator ML-265 inhibited ATRA-induced Neuro-2a and N1E-115 differentiation, whereas RNA interference-mediated Pkm silencing promoted Neuro-2a and N1E-115 differentiation, which was reversed by PKM overexpression...These results indicate that Wnt/β-catenin signaling promotes Neuro-2a and N1E-115 differentiation by inhibiting PKM-mediated glycolysis during ATRA-induced differentiation. These findings may provide a new theoretical basis for the role of glycolysis in nerve differentiation.

Taken together, NM enhanced the CBP sensitivity of ovarian cancer cells by promoting the ZNF24-mediated inactivation of the WNT2B/Wnt/β-catenin axis. These findings suggest a viable treatment approach for improving CBP resistance in ovarian cancer.

P1/2, N=89, Completed, Eisai Inc. | Active, not recruiting --> Completed

The WNT/β-catenin signaling pathway inhibitor, LGK974, inhibited WNT7B secretion, leading to GLUT1 levels downregulation and promotion of cell apoptosis. Ectopic tumor xenograft model experiments revealed that WNT7B promoted tumor progression in mice. Overall, our results suggest that WNT7B promotes β-catenin entry into the nucleus to initiates GLUT1 transcription, increases glucose transport and consumption, and enhances aerobic glycolysis, thus promoting tumor progression in colorectal cancer cells.

Moreover, XAV-939, a β-catenin inhibitor, was capable of suppressing the malignant phenotypes in TARDBP-overexpressed T-ALL cells...In aggregate, we explored a promising biomarker, TARDBP, for T-ALL treatment. The underlying mechanisms might involve the interaction with MDM2 mRNA and the regulation of the β-catenin pathway.

The current study reveals that PA-induced Porcupine disrupts lipid metabolism and promotes inflammatory response during MASLD development, which can be ameliorated by the Porcupine inhibitor Wnt974. Therefore, Porcupine may be a potential pharmacological target for the treatment of MASLD.

P1/2, N=301, Recruiting, Eisai Inc. | Phase classification: P1 --> P1/2 | N=181 --> 301 | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Mar 2027 --> Nov 2026

To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001...Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

P1, N=185, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Compound 4 also showed dramatic ability in suppressing oncogenic Wnt signaling to eliminate colorectal CSCs and inhibit tumor growth, with around 10- to 35-fold increased potency over IOX1. In summary, this study suggests that PROTACs provide a unique molecular tool for the development of novel small molecules from the IOX1 skeleton for selective degradation of KDM3 to eliminate colorectal CSCs via suppressing oncogenic Wnt signaling.

Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating β-catenin both in vitro and in vivo.

Finally, drug sensitivity analysis revealed that ALDOB increased the sensitivity of gastric cancer cells to most antitumor drugs, especially talazoparib, XAV939, and FTI-277. And ALDOB significantly inhibited proliferation and migration, delayed glycolysis in GC cells. Consequently, our study suggests that ALDOB may be a potential target for the clinical treatment of gastric cancer.

CHL-C is capable of inducing apoptosis and autophagy by influencing the Wnt/β-catenin signaling pathway.

Additionally, this is the first report of a RUNX1 fusion gene with the break point in intron 2, resulting in an out-of-frame fusion. Further research is needed to investigate the impact of this novel fusion on the establishment and progression of the disease.

Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model...These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.

This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.

It was also found that the upregulation of β-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939. The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/β-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.

APC and TP53 mutations were more frequent in the low LINC01550 expression group, while the high LINC01550 expression group was significantly more sensitive to 5-fluorouracil, irinotecan, trametinib, gemcitabine, rapamycin, and XAV939. LINC01550 exerted these effects by inhibiting Wnt/β-catenin signaling. Our results suggest LINC01550 as a diagnostic and prognostic predictor in CRC that acts as a tumor suppressor and a potential therapeutic target.

More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/β-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Moreover, SKL2001, a Wnt/β-catenin activator, partially abrogated the effects of TROAP silencing on EC cell proliferation and apoptosis, while the signaling inhibitor XAV-939 had the opposite effect. In conclusion, TROAP knockout retarded proliferation and elicited apoptosis in EC cells by blocking the Wnt/β-catenin pathway.

Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice...The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

In the TNBC cells, AQP5 modulates the expression levels of EMT-related proteins through activation of Wnt/β-catenin signaling pathway, thus enhancing the cell proliferation, migration and invasion while inhibiting the cell apoptosis.

In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/β-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.