A phase Ib/II multi-center, open label, dose escalation study of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant metastatic colorectal cancer harboring Wnt pathway mutations

Start Date18 Dec 2014

Sponsor / Collaborator

Array BioPharma, Inc.

NCT02278133 / CompletedPhase 1/2

A Phase Ib/II Multi-center, Open Label, Dose Escalation Study of WNT974, LGX818 and Cetuximab in Patients With BRAFV600-mutant KRAS Wild-type Metastatic Colorectal Cancer Harboring Wnt Pathway Mutations

The purpose of this study is to assess the safety and anti-tumor activity of the triple combination of WNT974, LGX818 and cetuximab in BRAFV600-mutant mCRC with RNF43 mutations or RSPO fusions.
The design of this study is based upon the translational and pre-clinical data that suggest that Wnt pathway signals, increased due to RNF43 mutations or RSPO fusions, cooperate with the EGFR and BRAF signals to maintain the growth of BRAFV600 CRCs. Inhibition of these signals with the triple combination of WNT974, LGX818 and cetuximab may result in anti-tumor activity.

Start Date01 Dec 2014

Sponsor / Collaborator

Array BioPharma, Inc.

NCT01351103 / CompletedPhase 1

A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands

The primary purpose of this study was to find the recommended dose of LGK974 as a single agent and in combination with PDR001 that can be safely given to adult patients with selected solid malignancies that had progressed despite standard therapy or for which no effective standard therapy existed.

Start Date01 Dec 2011

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with LGK-974

100 Translational Medicine associated with LGK-974

100 Patents (Medical) associated with LGK-974

Literatures (Medical) associated with LGK-974

01 Sep 2024·Drug Resistance Updates

Increased oxygen stimulation promotes chemoresistance and phenotype shifting through PLCB1 in gliomas

Article

Author: Yang, Chuanyan ; Chen, Tunan ; Lu, Yongling ; Li, Fei ; Mu, Ning ; Ma, Kang ; Feng, Hua ; Zeng, Lan ; Hu, Rong ; Liu, Yan ; Yang, Yang ; Bian, Xiuwu ; Chen, Yujie ; Quan, Yulian ; Xu, Kai ; Chen, Beike ; Shi, Yaning ; Li, Lan ; Ma, Yingjie ; Wang, Shi ; Lai, Ying ; Wang, Xiaoming

Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of β-catenin and active-β-catenin by increasing the proportion of ubiquitinated β-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-β-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. 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. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. 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.

01 Apr 2024·Drug Development Research

The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide

Article

Author: Kaya‐Yasar, Yesim ; Sezen, Sena F. ; Inan, Cihan ; Engin, Seckin ; Erkoseoglu, Ilknur ; Saygin, Ismail ; Barut, Elif Nur

AbstractThe wingless/integrase‐1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic‐acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA‐Al(OH)3administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK‐974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5‐HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5‐HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5‐HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK‐3β and WNT5A levels, which had been induced by airway inflammation, in a dose‐dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad‐2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin‐17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK‐3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.

28 Mar 2024·JBMR Plus

Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone

Article

Author: Hsiao, Edward C ; Ram, Apsara ; Ganesh, Gauri ; Ho, Sunita ; Kang, Misun ; Lung, Hsuan ; Zamarioli, Ariane ; Moody, Tania ; Wentworth, Kelly L

AbstractG protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single-cell RNA sequencing on long-bone stromal cells of 9-wk-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or downregulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.

News (Medical) associated with LGK-974

11 Oct 2022

·www.prnewswire.com

Esophageal Cancer Clinical Trial Pipeline Insights Featuring 80+ Companies | DelveInsight

The prevalence of esophageal cancer has been rising since the past few years, which prompts the growing demand for the treatment options. The market is driven by the increasing prevalence of cancer and the increase in research & development. The Companies developing the potential therapies in the last stage of development include Celgene,Jiangsu HengRui Medicine Co., Seagen, and several others. LAS VEGAS, Oct. 11, 2022 /PRNewswire/ -- DelveInsight's ' Esophageal Cancer Pipeline Insight – 2022 ' report provides comprehensive global coverage of available, marketed, and pipeline esophageal cancer therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the esophageal cancer pipeline domain. Key Takeaways from the Esophageal Cancer Pipeline Report DelveInsight's esophageal cancer pipeline report depicts a robust space with 80+ active players working to develop 90+ pipeline therapies for esophageal cancer treatment. Leading esophageal cancer companies such as Shanghai Henlius Biotech, CStone Pharmaceuticals, Jiangsu HengRui Medicine Co., Ltd., AstraZeneca, Symphogen, Hoffmann-La Roche, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Sinocelltech Ltd., Eli Lilly and Company, Ipsen, Jacobio Pharmaceuticals Co., Ltd., Shire, GlaxoSmithKline, Keythera Pharmaceuticals (Australia) Pty Ltd, Sunshine Lake Pharma Co., Ltd., Novartis Pharmaceuticals, Sanofi, Seagen Inc., Rapa Therapeutics LLC, Incyte Corporation, Atreca, Inc., Exelixis, Bayer, BeiGene, Lyell Immunopharma, Sichuan Baili Pharmaceutical, AP Biosciences.,Leap Therapeutics, Inc., Adlai Nortye Biopharma Co., Ltd., Athenex, Inc., Pfizer, Genentech, Hangzhou Neoantigen Therapeutics, Janssen Pharmaceutical, Curis, Inc.,Merck KGaA, Apexigen, Inc,Shenzhen Hornetcorn Bio-technology Company, LTD, MacroGenics, Bristol-Myers Squibb, Integral Molecular, CARTEXELL, EMD Serono, and others are evaluating new drugs for esophageal cancer treatment. Key esophageal cancer pipeline therapies in various stages of development include Serplulimab, CS1001, Camrelizumab, Durvalumab, Sym021, Spartalizumab, Sym022, Sym023, Regorafenib, S095033, INCB099318, RO7121661, XB002, LGK974, Abemaciclib, ladiratuzumab vedotin, ATRC-101, SGN-PDL1V, RO7247669, THOR-707, Letetresgene Autoleucel, TNO155, Anlotinib Hydrochloride, Larotinib, SCT-I10A, KF-0210, SCT200, Ramucirumab, Cabozantinib, JAB-3068, Onivyde, JAB-3312, SGN-B6A, RAPA-201,Ociperlimab, SI B001,Apatinib, AP 203, QEQ278, JAB-3312, DKN-01, AN0025, HR 070803,Oraxol, Sunitinib malate, Tiragolumab, iNeo Vac P01, Amivantamab, CA-4948, M1231, APX005M, DC-CIK, Margetuximab, Temozolomide, and others. In September 2022, Daiichi Sankyo and Sarah Cannon Research Institute (SCRI) announced that extended follow-up data from a phase I/II trial of DS-7300, continued to show promising durable tumor response in patients with several types of heavily pretreated cancers including lung, prostate or esophageal cancer.A response rate of 32% (95% CI: 24-41) was observed with 38 responses (33 confirmed; 28%; 95% CI: 20-37) in 118 patients with various solid tumors including small cell lung cancer (SCLC), squamous non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (CRPC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC) or endometrial cancer receiving doses of DS-7300 ranging from 4.8 mg/kg to 16.0 mg/kg. In September 2022, Integral Molecular, has licensed a panel of monoclonal antibodies (MAbs) to CARTEXELL, enabling CARTEXELL to develop CAR-T cell therapies using Integral Molecular's Claudin 18.2 (CLDN18.2) MAbs. Under the terms of the agreement, Integral Molecular will provide an exclusive worldwide license to CARTEXELL to use the panel of high-affinity, high-specificity, and fully humanized CLND18.2 MAbs for the development of CAR-T cell therapies against solid tumors including gastric, lung, pancreatic and esophageal cancers. CARTEXELL will be solely responsible for all research, development, and commercial activities. In August 2022, BeiGene announced that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted a supplemental biologics license application (sBLA) for tislelizumab in combination with chemotherapy as first-line treatment in patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC). In May 2022, Shanghai Junshi Biosciences Co., Ltd, announced that the China National Medical Products Administration (NMPA) has approved the supplemental new drug application (sNDA) for toripalimab in combination with paclitaxel and cisplatin in the first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic esophageal squamous cell carcinoma (ESCC). The sNDA was accepted by the NMPA in July 2021. This is the fifth indication approved for toripalimab in China and will benefit Chinese patients with advanced ESCC. In May 2022, Bristol Myers Squibb, announced that the U.S. Food and Drug Administration (FDA) has approved both Opdivo (nivolumab) (injection for intravenous use) in combination with fluoropyrimidine- and platinum-containing chemotherapy and Opdivo plus Yervoy (ipilimumab) as a first-line treatment for adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) regardless of PD-L1 status. The approvals are based on the Phase III CheckMate -648 trial, which evaluated Opdivo in combination with chemotherapy (n=321) and Opdivo plus Yervoy (n=325) each compared to chemotherapy alone (n=324), and was the largest Phase III trial of immunotherapy in first-line ESCC. In January 2022, Lyell Immunopharma, Inc., announced that the U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application to initiate a Phase I clinical trial for LYL132, an investigational T-cell receptor (TCR) therapy for patients with solid tumors expressing New York esophageal squamous cell carcinoma 1 (NY-ESO-1) that the company is developing in collaboration with GSK. Request a sample and discover the recent advances in esophageal cancer treatment @ Esophageal Cancer Pipeline Report The esophageal cancer pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage esophageal cancer drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the esophageal cancer pipeline landscape. Esophageal Cancer Overview Esophageal cancer grows in the esophagus, the tube that connects the throat to the stomach. Tumors develop in the mucosa, the inner lining of the esophagus. Esophageal cancer is classified into two types, each with its own set of risk factors: Adenocarcinoma -Adenocarcinomas are cancers that begin in gland cells at the bottom of the esophagus. This is the most common type of esophageal cancer. It usually happens near the stomach. The exact esophageal cancer causes are not known. Most esophageal cancer symptoms do not appear until cancer has progressed to an advanced stage, when it may be challenging to treat. Other, more common conditions can cause esophageal cancer symptoms. The most common esophageal cancer symptom is difficulty swallowing, particularly a sensation of food stuck in the chest. There are several tests used for esophageal cancer diagnosis. The most common include endoscopy with biopsy and endoscopic ultrasonography. Find out more about esophageal cancer drugs in development @ New Treatment for Esophageal Cancer A snapshot of the Esophageal Cancer Pipeline Drugs mentioned in the report: Learn more about the emerging esophageal cancer pipeline therapies @ Esophageal Cancer Clinical Trials Esophageal Cancer Therapeutics Assessment The esophageal cancer pipeline report proffers an integral view of esophageal cancer emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Esophageal Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Intra-articular, Intraocular, Intrathecal, Intravenous, Ophthalmic, Oral, Parenteral, Subcutaneous, Topical, Transdermal Therapeutics Assessment By Molecule Type: Oligonucleotide, Peptide, Small molecule Therapeutics Assessment By Mechanism of Action: Prostaglandin E EP4 receptor antagonists, ERBB 2 receptor antagonists, Phosphorylation inhibitors, Antibody-dependent cell cytotoxicity, Apoptosis stimulants, CD40 antigen stimulants, Immunostimulants, Programmed cell death-1 receptor antagonists, T lymphocyte stimulants, Programmed cell death-1 ligand-1 inhibitors, Epidermal growth factor receptor antagonists. Key Esophageal Cancer Companies: Shanghai Henlius Biotech, CStone Pharmaceuticals, Jiangsu HengRui Medicine Co., Ltd., AstraZeneca, Symphogen, Hoffmann-La Roche, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Sinocelltech Ltd., Eli Lilly and Company, Ipsen, Jacobio Pharmaceuticals Co., Ltd., Shire, GlaxoSmithKline, Keythera Pharmaceuticals (Australia) Pty Ltd, Sunshine Lake Pharma Co., Ltd., Novartis Pharmaceuticals, Sanofi, Seagen Inc., Rapa Therapeutics LLC, Incyte Corporation, Atreca, Inc., Exelixis, Bayer, BeiGene, Lyell Immunopharma, Sichuan Baili Pharmaceutical, AP Biosciences.,Leap Therapeutics, Inc., Adlai Nortye Biopharma Co., Ltd., Athenex, Inc., Pfizer, Genentech, Hangzhou Neoantigen Therapeutics, Janssen Pharmaceutical, Curis, Inc.,Merck KGaA, Apexigen, Inc,Shenzhen Hornetcorn Bio-technology Company, LTD, MacroGenics, Bristol-Myers Squibb, Integral Molecular, CARTEXELL and others Key Esophageal Cancer Pipeline Therapies: Serplulimab, CS1001, Camrelizumab, Durvalumab, Sym021, Spartalizumab, Sym022, Sym023, Regorafenib, S095033, INCB099318, RO7121661, XB002, LGK974, Abemaciclib, ladiratuzumab vedotin, ATRC-101, SGN-PDL1V, RO7247669, THOR-707, Letetresgene Autoleucel, TNO155, Anlotinib Hydrochloride, Larotinib, SCT-I10A, KF-0210, SCT200, Ramucirumab, Cabozantinib, JAB-3068, Onivyde, JAB-3312, SGN-B6A, RAPA-201,Ociperlimab, SI B001,Apatinib, AP 203, QEQ278, JAB-3312, DKN-01, AN0025, HR 070803,Oraxol, Sunitinib malate, Tiragolumab, iNeo Vac P01, Amivantamab, CA-4948, M1231, APX005M, DC-CIK, Margetuximab, Temozolomide and others. Dive deep into rich insights for esophageal cancer drugs, visit @ Chemo Drugs for Esophageal Cancer Treatment Table of Contents For further information on the esophageal cancer pipeline therapeutics, reach out @ New Drug for Esophageal Cancer Treatment Related Reports Esophageal Cancer Market Esophageal Cancer Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key esophageal cancer companies including Merck KGaA, Shenzhen Hornetcorn Biotechnology, Apexigen, Inc., Highlight Therapeutics, among others. Esophageal Cancer Epidemiology Forecast Esophageal Cancer Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted esophageal cancer epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Esophageal Squamous Cell Carcinoma Pipeline Esophageal Squamous Cell Carcinoma Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key esophageal squamous cell carcinoma companies, including BeiGene, AstraZeneca, Ipsen, Shire, Sanofi, Seagen, among others. Esophageal Squamous Carcinoma Market Esophageal Squamous Carcinoma Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key esophageal squamous carcinoma companies, including BeiGene, AstraZeneca, Ipsen, Shire, Sanofi, Seagen, among others. Esophageal Squamous Cell Carcinoma Epidemiology Esophageal Squamous Cell Carcinoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted esophageal squamous cell carcinoma epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Other Trending Reports Goitre Market | Thymus Cancer Market | US Healthcare Outlook Report | Venous Stenosis Market | Negative Pressure Wound Therapy Systems Market | Global Kinase Inhibitor in Autoimmune Diseases Market | Metrorrhagia Market | Dysfunctional Uterine Bleeding Market | Hypereosinophilic Syndrome Market | Age-related Vision Dysfunction Market | Dental Lasers Market | CRISPR Therapies Pipeline Insight | Cell And Gene Therapy For Multiple Myeloma Market | Drug Hypersensitivity Market | Dysthymia Market | Persistent Depressive Disorder Market | Cancer Vaccines Market | Weight Loss/Weight Management (Obesity) Market | Food Allergy Market | Obsessive-Compulsive Disorder Market | Tumor Ablation Market | Physiotherapy Equipment Market | Chimeric Antigen Receptor (CAR) T-Cell Therapy Market | Anti-hypertension Market | Radiofrequency Ablation Devices Market | Global Messenger RNA (mRNA)-based Vaccines and Therapeutics Market | Gastro Intestinal Bleeding Market | Trastuzumab Biosimilars Insight | Varicose Veins Market | Germ Cell Tumor Market | Intracardiac Echocardiography Devices Market | India Healthcare Report | Crows Feet Market | Seborrhoeic Dermatitis Market | Injectable Drug Delivery Devices Market | Structural Heart Devices Market | Substance (Drug) Abuse Market | Insulin Glargine Biosimilar Insight About DelveInsight DelveInsight is a leading Business Consultant, and Market Research firm focused exclusively on life sciences. Connect with us at LinkedIn Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

Gene TherapyAntibodyBiosimilarOligonucleotideCell Therapy

16 Aug 2022

·www.sciencedaily.com

New cryo-EM images shed light on Wnt signaling

Researchers have captured images of an enzyme for Wnt lipidation, which is pivotal to human development and cancer and crucial for Wnt signaling activation. The findings shed light on the mechanisms behind this activity and could eventually lead to new drugs to treat various malignancies. Using UT Southwestern's Cryo-Electron Microscopy Facility, researchers have captured images of an enzyme for Wnt lipidation, which is pivotal to human development and cancer and crucial for Wnt signaling activation. The findings, reported in Nature, shed light on the mechanisms behind this activity and could eventually lead to new drugs to treat various malignancies. "We are able to push the research envelope further into the key area of cancer-related signaling pathways thanks to UT Southwestern's state-of-the-art cryo-electron microscopy (cryo-EM) facility," said Xiaochun Li, Ph.D., Associate Professor of Molecular Genetics and Biophysics, who co-led the study with Yang Liu, a fourth-year graduate student, and Xiaofeng Qi, Ph.D., a postdoctoral researcher. Both Mr. Liu and Dr. Qi work in the Li lab. "The revealed scientific mechanism could accelerate the development of novel cancer-fighting drugs toward advanced solid tumors." Scientists have long known that members of the Wnt family of proteins are pivotal for embryonic development, kicking off signaling pathways necessary for functions such as axis formation, cell fate specification, and cell proliferation and migration. When Wnt proteins were first discovered in the early 1980s, they were immediately associated with cancer; aberrant Wnt signaling is known to contribute to pancreatic cancer, melanoma, triple-negative breast cancer, and other types of malignancies. To perform their signaling functions, Dr. Li explained, Wnt proteins must first be activated by the addition of a lipid molecule, a job performed by an enzyme called Porcupine (PORCN). How this occurs structurally and the mechanism by which investigational drugs inhibit this activity have been unknown. To investigate, Dr. Li and his colleagues gathered cryo-EM images of four structures: PORCN bound to a co-enzyme called palmitoleoyl-CoA, which contributes the lipid molecule to activate Wnt; PORCN bound to LGK974, an investigational drug known to inhibit Wnt signaling; PORCN bound to LGK974 and WNT3A, a Wnt family member; and PORCN bound to an activated, lipid-modified WNT3A protein. Cryo-EM, a technique recognized by a 2017 Nobel Prize, freezes proteins in place to get atomic-resolution microscopic images. These images showed that WNT3A, PORCN, and palmitoleoyl-CoA come together in a sandwich-type configuration, with PORCN in the middle flanked by the two other precursors. When WNT3A and PORCN were incubated with LGK974 instead of palmitoleoyl-CoA, the investigational drug took the place of the palmitoleoyl-CoA, blocking its ability to bind and contribute the lipid molecule; without this lipid modification, Dr. Li said, WNT3A can't set off a signaling cascade. Additionally, the images solved a decades-old mystery as to why the lipid chain that modifies Wnt proteins differs structurally from that on a related protein called Hedgehog, which is also involved in human development and cancer and activated by lipid modification. While the lipid chain on Hedgehog is made of a saturated fatty acid, causing it to extend into a straight line, the one on PORCN is unsaturated, causing it to kink into a C-shape. The researchers found that this kink is necessary for the lipid chain to fit into a cavity on PORCN, a critical step before transferring it onto Wnt. Dr. Li noted that LGK974 is one of several drugs that affect Wnt signaling that is currently in clinical trials against various cancers. Knowing the atomic structures of Wnt, PORCN, palmitoleoyl-CoA, and their complexes could lead to drugs better designed to block these interactions. Dr. Li is a Rita C. and William P. Clements, Jr. Scholar in Biomedical Research. Other researchers who contributed to this study include Linda Donnelly, Tao Long, Rich W. Zhou, Yingyuan Sun, and Boyuan Wang of UTSW; and Nadia Elghobashi-Meinhardt of Technical University Berlin in Germany. This work was supported by grants from the Damon Runyon Cancer Foundation (DRR-53S-19), the National Institutes of Health (P01 HL020948, P01 HL160487, R01 GM135343), The Welch Foundation (I-1957), and the Life Sciences Research Foundation. Cryo-EM data were collected at the UT Southwestern Medical Center Cryo-EM Facility, funded in part by an award from the Cancer Prevention and Research Institute of Texas (RP170644).

100 Deals associated with LGK-974

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
KRAS Wild-type Colorectal Cancer	Discovery	BE	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	IT	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	SG	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	ES	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	FR	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	CA	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	IL	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	NL	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	AU	Array BioPharma, Inc.	01 Dec 2014
KRAS Wild-type Colorectal Cancer	Discovery	US	Array BioPharma, Inc.	01 Dec 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01351103 (ESMO2024) Manual	Phase 1	Melanoma, Cutaneous Malignant	42	WNT974+spartalizumab	(lflnjqsxwv) = The 2 most common TRAEs of any grade were nausea (23.8%) and alopecia (19%); 6 pts had Grade 3/4 TRAEs (increased lipase, n=4, increased amylase, n = 2, increased blood bilirubin, n = 1 and immune-mediated gastritis, n = 1); no TRAE was fatal. zywnjvkkhg (mcbolgeqxi ) View more	Positive	15 Sep 2024
NCT01351103 (Pubmed \| Med J Aust) Manual	Phase 1	Neoplasms	94	WNT974	(mufbrsvxvs) = Dysgeusia（50%） ifjstfndpe (jeuwssezef ) View more	Positive	01 Jul 2021
NCT01351103 (AACR2020) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	27	LGK-974+spartalizumab	(ntbmomsrlw) = NE mgvjpigapj (wogobqnmeb ) View more	Positive	27 Apr 2020

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