WNT974 / Novartis - LARVOL DELTA

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (SNO 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (SNO 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

NF2/Merlin loss induces upregulation of an alternative Wnt5a/b signaling pathway sensitive to YAP inhibition (SNO 2025) - "In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo"

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • Cognitive Disorders • Meningioma • Movement Disorders • Otorhinolaryngology • Solid Tumor • Ventriculomegaly • CTNNB1 • NF2

Wnt5a Regulates Focal Adhesion Formation to Promote Migration in Ewing Sarcoma. (PubMed, Cancers (Basel)) - "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."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • VCL

Wnt5a-mediated Adipo-Cardiac Interorgan Communication in HFpEF. (PubMed, bioRxiv) - "Wnt5a exposure increased cardiomyocyte hypertrophy in vitro , and LGK974 (PORCN inhibitor) treatment in vivo decreased circulating Wnt5a levels and improved cardiac remodeling in HFpEF. Our study identifies a novel crosstalk mechanism between cardiomyocytes and adipocytes in obesity-associated HFpEF driven by natriuretic peptide-mediated inhibition of release of Wnt5a from adipocytes."

Journal • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Obesity • NPR3 • WNT5A

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (WFNOS 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • CD8 • GZMB • WNT7B

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (WFNOS 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

NF2/Merlin loss induces upregulation of an alternative Wnt5a/b signaling pathway sensitive to YAP inhibition (WFNOS 2025) - "In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo"

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • CNS Tumor • Cognitive Disorders • Meningioma • Movement Disorders • Oncology • Otorhinolaryngology • Solid Tumor • Ventriculomegaly • CTNNB1 • NF2

B4GALT1 and Wntless collaborate to block LRP5/6 translocation from Golgi to cell surface. (PubMed, J Cell Biol) - "Accordingly, LGK974-targeted uncoupling of the Wnt/Wntless complex is able to enhance LRP5/6 Golgi retention, thereby attenuating LRP5/6 cell surface translocation. Taken together, the surface presentation of LRP5/6 is regulated by the Golgi-resident B4GALT1 as well as the Wnt secretion activity."

Journal • Dyslipidemia

BUB1B Promotes Ovarian Cancer Cell Proliferation and Metastasis by Activating the Wnt/β-Catenin Pathway. (PubMed, Cancer Med) - "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."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BUB1 • BUB1B

Inhibition of Wnt Signaling Attenuates Inflammatory Arthritis Severity (ACR Convergence 2025) - "Mice were given daily intraperitoneal injections of the Wnt signaling inhibitor LGK974 or a vehicle control on days 0-4... Collectively, our findings demonstrate the utility of Wnt pathway inhibition in reducing inflammatory arthritis severity. This work identifies a novel fibroblast-targeted therapeutic avenue for RA with a compelling potential value for patients whose disease is recalcitrant to conventional treatment modalities."

Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CXCL5 • SOCS1 • SOCS3

Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma. (PubMed, Proc Natl Acad Sci U S A) - "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."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD8 • WNT7B

EXPRESS: Exacerbation of paclitaxel-induced neuropathic pain behaviors in breast tumor-bearing mice. (PubMed, Mol Pain) - "Paclitaxel-induced neuropathic pain model in breast tumor-bearing female MMTV-PyMT mice may be a useful animal model for investigating the analgesic effects and underlying mechanisms for CINP in breast cancer patients as well as the interplay between CINP development and cancer progression."

Journal • Preclinical • Breast Cancer • Neuralgia • Oncology • Pain • Solid Tumor

Injectable Ca2+/Sr2+-crosslinked hydrogel with sustained release of LGK-974 for cartilage repair and osteoarthritis prevention via alleviating inflammatory microenvironment. (PubMed, Mater Today Bio) - "In vivo studies further confirmed that the hydrogel significantly promoted cartilage repair and stimulated ECM regeneration. Building on the pathogenesis of OA, this study suggests that the novel injectable hydrogel holds great promise as an effective therapeutic strategy for promoting cartilage repair and preventing OA progression through minimally invasive intervention."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

Bone Toxicity Case Report Combining Encorafenib, Cetuximab and WNT974 in a Phase I Trial. (PubMed, Anticancer Res) - P1/2 | "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."

Journal • P1 data • Colorectal Cancer • Endocrine Disorders • Metabolic Disorders • Musculoskeletal Diseases • Oncology • Sarcoma • Solid Tumor • KRAS • RNF43

Porcupine inhibition enhances hypertrophic cartilage differentiation. (PubMed, JBMR Plus) - "To uncover the mechanism of PORCN action during chondrogenesis, we used 2 different PORCN inhibitors, C59 and LGK974, in several model systems, including micromasses, 3D cell cultures, long bone tissue cultures, and zebrafish animal model...In summary, our results provide evidence of the distinct role of PORCN in both the early and late stages of cartilage development. Further, our data demonstrate that PORCN inhibitors can be used in the experimental and clinical strategies that need to trigger chondrocyte differentiation and/or cartilage outgrowth."

Journal • WNT3A

Porcupine inhibition is a promising pharmacological treatment for severe sclerosteosis pathologies. (PubMed, Bone Res) - "Interestingly, the target engagement biomarker Axin2 was only significantly reduced in male vertebrae, which may indicate differences in male and female response to LGK974. This study also shows that PORCN inhibition may effectively limit characteristic HBM and skeletal overgrowth in sclerosteosis patients at sites with severe pathology."

Journal • CNS Disorders • Otorhinolaryngology • Rare Diseases • AXIN2 • RUNX2 • SOST

Dual role of WNT10A in promoting the malignancy of glioblastoma and remodeling the tumor microenvironment. (PubMed, Neuro Oncol) - "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."

Biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • IL6

Deciphering the value of anoikis-related genes in prognosis, immune microenvironment, and drug sensitivity of laryngeal squamous cell carcinoma. (PubMed, Pathol Res Pract) - "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."

Journal • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MMP3 • TIMP1

The effects of the Wnt/β-catenin signaling pathway on the in vitro differentiation of rat BMSCs into leydig cells. (PubMed, Sci Rep) - "BMSCs were divided into three groups: Control, Wnt agonist (CHIR-99021), and Wnt inhibitor (LGK-974), each incubated for 14 days...We verified that the Wnt/β-catenin signaling pathway is involved in this differentiation process. The idea proposed in our study for efficiently inducing differentiation of BMSCs into LC in vitro, may provide a safe and sustainable LC source for developing clinically feasible cell transplantation-based LOH therapies."

Journal • Preclinical • Endocrine Disorders • Transplantation • CD44 • ITGB1 • PTPRC • THY1

Porcupine expression promotes the progression of oral carcinogenesis. (PubMed, Neoplasia) - "Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Porcupine inhibitors LGK-974 and ETC-159 inhibit Wnt/β-catenin signaling and result in inhibition of the fibrosis. (PubMed, Toxicol In Vitro) - "LGK-974 and ETC-159 may be a possible long-term therapeutic target for scleroderma."

Journal • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • TGFB1

Epithelial cell adhesion molecule induces induces Wnt receptor transcription to promote colorectal cancer progression (COSA 2024) - "Our EpCAM-neutralizing antibody (EpAb2-6) and a porcupine inhibitor (LGK974) each partially attenuated cancer stemness, while their combination abolished stemness-related endpoints, induced apoptosis in vitro and markedly diminished tumor progression in animal models of human CRC. From these findings, we conclude that EpCAM stimulates Wnt signaling to promote cancer stemness, and the combination of EpAb2-6 and porcupine inhibitors may represent an effective CRC treatment, including for KRAS-mutant cancers. Thus, the mechanistic insights gained from our study may be useful to improve existing treatments or to develop novel anticancer therapeutics."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FZD6 • KRAS

Activation of the WNT7B/β-Catenin Pathway Initiates GLUT1 Expression and Promotes Aerobic Glycolysis in Colorectal Cancer Cells. (PubMed, Nutr Cancer) - "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."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • SLC2A1 • WNT7B

Elevated Porcupine Disrupts Lipid Metabolism and Promotes Inflammatory Response in MASLD. (PubMed, Liver Int) - "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."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • CD36 • SCARB1