WNT974 / Novartis - LARVOL DELTA

Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. (PubMed, Exp Ther Med) - "Although antifibrotic agents such as pirfenidone and nintedanib can slow disease progression, these agents fail to reverse established structural damage, underscoring the urgent need for novel therapeutic strategies...The present study aimed to elucidate the role of WNT signaling in IPF pathogenesis, and to evaluate the antifibrotic and anti-inflammatory effects of the WNT inhibitors ETC-159 and LGK-974 in vitro...In conclusion, aberrant activation of WNT signaling may contribute to fibrogenesis and inflammation in IPF. Pharmacological inhibition of this pathway, particularly with LGK-974, exerts potent antifibrotic and anti-inflammatory effects, highlighting WNT signaling as a viable therapeutic target for IPF."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • IL1B • IL6 • TGFB1 • WNT7A

Targeting circGDI2 disrupt HNRNPC-mediated mPORCN stabilization and enhance LGK-974 anti-tumor therapy in hepatocellular carcinoma. (PubMed, Mol Cancer) - No abstract available

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • HNRNPC

FOXK1 induced upregulation of KIF20A promotes hepatocellular carcinoma progression via Wnt/β-Catenin/EMT signaling. (PubMed, Cell Mol Life Sci) - "Wnt pathway activator SKL2001 and inhibitor LGK974 confirmed KIF20A's role in tumor progression...ChIP-seq and promoter assays verified FOXK1's direct binding to the KIF20A promoter, activating its transcription. In conclusion, KIF20A serves as a diagnostic and prognostic biomarker promoting HCC progression via Wnt/β-catenin signaling, regulated by FOXK1, offering new therapeutic targets."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CDH2 • KIF11 • KIF13A • KIF20A • KIF5B • SNAI2 • TWIST1

Regulation of the AKT/Wnt/β-catenin Pathway and Induction of Cuproptosis by Curcumin in Glioblastoma. (PubMed, J Vis Exp) - "A172 and U251 cells were treated with CUM, AKT inhibitor MK-2206, Wnt inhibitor LGK974, and Elsm-Cu (Elesclomol + CuCl2). In nude mice, CUM significantly reduced tumor growth, promoted cuproptosis, and inhibited AKT/Wnt/β-catenin axis activation. Our results indicate that CUM suppresses AKT/Wnt/β-catenin signaling, promotes cuproptosis, and interferes with GBM progression."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Phase I study of WNT974 in combination with spartalizumab in patients with cutaneous melanoma (ESMO 2024) - P1 | "WNT974 + spartalizumab was well-tolerated and demonstrated preliminary antitumor activity in pts with advanced melanoma who progressed on prior anti-PD-1-based therapy."

Clinical • Combination therapy • IO biomarker • P1 data • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Single-cell and immune-context integration identifies basement-membrane/metastasis signatures that sharpen bladder-cancer diagnosis and prognosis. (PubMed, Discov Oncol) - "The MBRG-based model effectively predicts BLCA prognosis, integrates mechanisms of basement membrane remodeling, EMT, and immune suppression, and identifies DDR2 and SERPINF1 in CAFs as potential targets for personalized therapy."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • CD8 • DDR2 • HSPG2 • SLIT2 • TMB

Targeting the tumor cell-intrinsic ITGB2 axis inhibits melanoma progression. (PubMed, Mol Cancer) - "This work overturns the longstanding paradigm that ITGB2 is restricted to leukocytes by discovering a tumor cell-intrinsic ITGB2:ICAM-1:Wnt protumorigenic axis as a bona fide cancer therapeutic target in melanoma."

Journal • Melanoma • Solid Tumor • ICAM1 • IL2 • ITGB2

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