WNT974

We have previously reported that WNT974, a selective Porcn inhibitor, delays the onset of metastases in three different xenograft models of Ewing sarcoma with no effect on primary tumor growth, suggesting a specific role of the drug in metastasis...Crispr-Cas9 editing of Wnt5a results in an inability of the cells to migrate with a global lack of filamentous actin in the cell cytoskeleton. These findings suggest that a Wnt5a-dependent signaling pathway drives the cytoskeletal changes and cell adhesion molecule changes necessary for early steps of migration in the metastatic cascade.

BUB1B is an oncogene whose expression level is negatively correlated with the prognosis of OC patients. Mechanically, BUB1B promotes the progression of OC via the Wnt/β-catenin pathway. Our study offers a potential therapeutic target for OC treatment.

Treatment combining a porcupine inhibitor WNT974 with αPD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors...Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/β-catenin inhibition with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling.

The two patients described developed severe bone toxicities including rib fractures, a toe fracture, osteoporotic thoracic collapses, hypercalcemia, and alternated bone biomarkers. These cases highlight the potential skeletal risks associated with dual MAPK and WNT pathway inhibition.

Our findings revealed that WNT10A is a critical factor promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.

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.

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.

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

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.

Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/β-catenin signaling pathway.Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 µM) and 15 µM Wnt3a inhibitor (LGK974) for 48 h...TQ can increase intracellular accumulation of Rhodamine 123, indicating the inhibition of efflux mechanisms in cancer cells. Along with these changes, the migration of cells was also reduced (p < 0.05).TQ is a potential phytocompound to alter the dynamic growth of human colorectal HT-29 cells via the modulation of autophagy, and mitophagy-related mechanisms.

In conclusion, we developed a novel T cell exhaustion-associated signature, which holds considerable predictive value for both the prognosis of patients with HNSCC and the effectiveness of tumor immunotherapy.