IMCnyeso / GSK, Immunocore - LARVOL DELTA

STUDY OF FATTY ACIDS PROMOTING LYMPHOVASCULAR SPACE INVASION IN ENDOMETRIAL CANCER THROUGH ITGB3-ICAM1-TRPV4 MEDIATING MECHANICAL CROSSTALK BETWEEN CANCER CELLS AND ENDOTHELIAL CELLS (IGCS 2025) - "Transendothelial migration of EC cells could be stimulated by GSK101, an activator of TRPV4, and this effect was not seen after knockdown of TRPV4 in endothelial cells... Dyslipidemia could promote the development of LVSI in mice. The transendotheial migration of EC cells was promoted by free fatty acids, which might be related to the upregulation of ITGB3. The expression of ITGB3 in EC cells was elevated to induce clustering of ICAM-1 to increase mechanical forces in endothelial plasma membrane, to activate the mechanosensitive cation channel TRPV4."

Endometrial Cancer • Oncology • Sarcoma • Solid Tumor • ICAM1 • ITGB3 • TYK2

Identification of Novel Selective Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists. (PubMed, Curr Pharm Des) - "Our study provides new insight into the role of TRPV4 in pain and itch sensation and introduces LM0038, the most potent agonist, as a novel alternative to GSK101. With enhanced biological activity, it may serve as a valuable tool for studying TRPV4 function."

Journal • Pain

TRPV4 inhibition suppresses myocardial ischemic-reperfusion arrhythmia of mice by alleviating calcium handling abnormalities. (PubMed, Heart Rhythm) - "TRPV4 inhibition exerts antiarrhythmic effects post-IR by modulating CaMKII-dependent Ca2+ handling abnormalities, reducing CaT alternans and Ca2+ leak, without affecting APD."

Journal • Preclinical • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • Ventricular Tachycardia

The non-artemisinin antimalarial drugs under development: a review. (PubMed, Clin Microbiol Infect) - "Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health effort toward malaria control, elimination, and, potentially, eradication."

Journal • Review • Infectious Disease • Malaria

Phase 1 study of IMCnyeso, a T cell receptor bispecific ImmTAC targeting NY-ESO-1-expressing malignancies. (PubMed, Cell Rep Med) - P1/2 | "IMCnyeso is well tolerated and, at doses ≥30 μg, induces pharmacodynamic changes consistent with T cell redirection. This study was registered at ClinicalTrials.gov (NCT03515551)."

Journal • P1 data • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Synovial Sarcoma • CTAG1B • CTAG2 • HLA-A

Differential editing efficiencies in cereal crops: a comparative analysis of tRNA and ribozyme multiplexed guide delivery. (PubMed, Front Plant Sci) - "Stable inheritance is also achievable in all three species when plants are sampled shortly after the tissue culture concludes. Overall, inheritance rates were above 85% in all three species, particularly when mutations are detected early after plants emerge from tissue culture."

Journal

A phase 1b study to characterize the safety and pharmacokinetic/pharmacodynamic relationship of MMV367 (GSK701) in adult participants experimentally infected with blood- stage Plasmodium falciparum (ASTMH 2024) - P1 | "All 6 participants received rescue treatment with artemether-lumefantrine by day 4 post administration of MMV367 and recrudescences allowed identification of the PK/PD relationship. There were no serious adverse events. In summary, this study supports the further clinical development of MMV367 in patients as a single dose treatment of uncomplicated malaria."

Clinical • P1 data • PK/PD data • Infectious Disease • Malaria

STUDY OF FATTY ACIDS PROMOTING LYMPHOVASCULAR SPACE INVASION IN ENDOMETRIAL CANCER THROUGH ITGB3-ICAM1-TRPV4 MEDIATING MECHANICAL CROSSTALK BETWEEN CANCER CELLS AND ENDOTHELIAL CELLS (IGCS 2024) - "Transendothelial migration of EC cells could be stimulated by GSK101, an activator of TRPV4, and this effect was not seen after knockdown of TRPV4 in endothelial cells... Dyslipidemia could promote the development of LVSI in mice. The transendotheial migration of EC cells was promoted by free fatty acids, which might be related to the upregulation of ITGB3. The expression of ITGB3 in EC cells was elevated to induce clustering of ICAM-1 to increase mechanical forces in endothelial plasma membrane, to activate the mechanosensitive cation channel TRPV4."

Endometrial Cancer • Oncology • Sarcoma • Solid Tumor • ICAM1 • ITGB3 • TYK2

Safety of neoadjuvant PARP inhibitor and immunotherapy in locally advanced HPV-negative head and neck squamous cell carcinoma (PRIME H&N Study) (ESMO 2024) - "The PRIME trial evaluates combination of dostarlimab (D) and niraparib (N) as neoadjuvant and adjuvant treatment for LA HPV-negative HNSCC...Delay in surgery was observed [GSK1] [PB2] in 1 pts (10 days) due to elevation of CK and troponin T, that were not linked to any cardiac event. The PRIME trial demonstrated acceptable safety and tolerability of study treatment. Translational data and primary endpoint analysis are still ongoing to define study treatment efficacy."

Clinical • Metastases • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Transient Receptor Potential Vanilloid 4 Activation Within the Oral Cancer Microenvironment (IASP 2024) - "For all concentrations above 10nM GSK101 the response of SCs to the agonist was at least 50% greater than DOK and HSC-3, which did not differ in response (p<0.01, 1-way ANOVA, n = 8 wells)... TRPV4 is expressed on SC and oral cancer cells found within the cancer microenvironment. The responses of SCs, DOK, and HSC-3 to the TRPV4 agonist were robust and dose dependent. The TRPV4 response on SC is greater than DOK and HSC-3."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • Squamous Cell Carcinoma • TRPV4

Exploring How TRPV4 Activity is Modulated in Schwann Cells (IASP 2024) - "TRPV4 is functionally expressed by human and mouse SC and TRPV4 activity in human SC is increased by cell swelling when going from a hypertonic environment to an isotonic one. Given that SC swelling, which deforms the cell membrane, sensitizes TRPV4 to its specific agonist GSK101, we plan to study how stiffness of the extracellular matrix can influence TRPV4 activity on SCs, since oral cancers exhibit increased tissue stiffness (3,4) which also causes deformation of the cell. We will explore whether modulation of extracellular matrix stiffness contributes to oral cancer pain through SC TRPV4."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • GAPDH • TRPV4

TRPV4 Activation in Schwann Cells Regulates Cathepsin S Activity: Role in Oral Cancer Pain (IASP 2024) - "The functional expression of TRPV4 on SCs was studied with whole-cell patch clamp and the selective TRPV4 agonist (GSK101) and TRPV4 antagonist (HC067)... TRPV4 is functionally expressed on SCs in nerve fibers that innervate the oral cancer in patients who report pain. TRPV4 activation on SCs increased the extracellular activity of CTSS. Our findings suggest a potential mechanism for oral cancer pain that depends on TRPV4 activation on SCs and CTSS extracellular activity."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • Tongue Carcinoma • CTSS • TRPV4

Tuning the Response of Synthetic Mechanogenetic Gene Circuits using Mutations in TRPV4. (PubMed, Tissue Eng Part A) - "Gene circuit output was dependent on the degree of TRPV4 activation secondary to GSK101 concentration or strain magnitude during loading. V620I constructs secreted more IL-1Ra compared to T89I across all experimental conditions, indicating that two mutations that cause similar functional changes to TRPV4 can result in distinct circuit activation profiles that differ from wild-type cells. In summary, we successfully demonstrate proof-of-concept that point mutations in TRPV4 that alter channel function can be used to tune the therapeutic output of mechanogenetic gene circuits."

Journal • Gene Therapies • TRPV4

LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling. (PubMed, J Cell Mol Med) - "Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice...Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification."

Journal • Dermatology • Infectious Disease • Pruritus • TLR4

TRPV4 mediates IL-1-induced Ca2+ signaling, ERK activation and MMP expression. (PubMed, FASEB J) - "Pre-incubation of cells with IL-1 Receptor Antagonist blocked Ca2+ entry induced by IL-1 or the TRPV4 agonist GSK101...The functional linkage of TRPV4 with IL-1R1 expands its repertoire of innate immune signaling processes by mediating IL-1-driven Ca2+ responses that drive matrix remodeling in fibroblasts. Thus, inhibiting TRPV4 activity may provide a new pharmacological approach for blunting matrix degradation in inflammatory diseases."

Journal • Inflammation • IL1B • MMP1 • MMP13 • TRPV4

EZH2 INHIBITION PRESERVES GASTRIC PACEMAKER CELL AND GASTRIC MOTOR FUNCTION DURING AGING (DDW 2024) - "To examine Ezh 's role in Kit-positive ICC lineage in mice Ezh gene was deactivated by tamoxifen (Tam) in Kit creERT /+ mice carrying Ezh fl/fl . Trp53 a key molecule for ICC aging was induced using nutlin 3a in both gastric muscle organotypic cultures (PMID: 37301443) and an ICC-SC cell line...GSK1 6 another EZH inhibitor and siRNA-mediated Ezh knock-down mimicked the effect of EPZ6438 in ICC-SC. Unexpectedly gastric EZH protein and H3K 7me3 levels gradually increased with age in human beings. Similarly elevated EZH and H3K 7me3 levels were observed in stomachs of naturally aged mice ( - 4 months old) and klotho mice. EPZ6438 treatment prevented the increase in H3K 7me3 and the reduction in the expression of the KIT ligand stem cell factor (SCF) by WB and restored gastric ICC decline by IHC."

Metabolic Disorders • Obesity • Sarcopenia • TP53

Voluntary wheel exercise improves glymphatic clearance and ameliorates colitis-associated cognitive impairment in aged mice by inhibiting TRPV4-induced astrocytic calcium activity. (PubMed, Exp Neurol) - "The present study reveals a novel role of voluntary exercise in alleviating colitis-related cognitive impairment and anxiety disorder, which is mediated by the promotion of AQP4 polarization and glymphatic clearance of Aβ via inhibition of TRPV4-induced astrocytic calcium hyperactivity."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Mood Disorders • Psychiatry • TRPV4

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx. (PubMed, Pharmaceuticals (Basel)) - "We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca2+]i, characterized by a slow onset and a plateau phase...We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca2+ and Na+, and the opening of L-VDCCs. The entry of Ca2+ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Modulation of TRPV4-mediated TNF-α expression in Müller glia and subsequent RGC apoptosis by statins. (PubMed, Exp Eye Res) - "Cells were pretreated with simvastatin or lovastatin before GSK101...Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma."

Journal • Glaucoma • Oncology • Ophthalmology • TNFA • TRPV4

Myoendothelial feedback in mouse mesenteric resistance arteries is similar between the sexes, dependent on nitric oxide synthase, and independent of TPRV4. (PubMed, Am J Physiol Heart Circ Physiol) - "Activation of TRPV4 with GSK101 (0.1-10 µM) induced similar dilation between the sexes...Similar expression of eNOS was found between the sexes with western blot. Thus, MEF is prominent and similar in murine 1 and 2 order mesenteric resistance arteries of both sexes, and reliant primarily on NOS, and secondarily on hyperpolarization, but not TRPV4."

Journal • Preclinical • NOS3

PIEZO1 is downregulated in glenohumeral chondrocytes in early cuff tear arthropathy following a massive rotator cuff tear in a mouse model. (PubMed, Front Bioeng Biotechnol) - " In native humeral head chondrocytes, chemical activation of PIEZO1 (Yoda1) significantly increased chondrocyte mechanical susceptibility against impact loads, while TRPV4 activation (GSK101) significantly decreased impact-induced chondrocyte death... In contrast to the hypothesis, PIEZO1 expression and activity is not increased, but rather downregulated, after massive RCT at the early stage of cuff tear arthropathy. These results may be secondary to the decreased axial loading after glenohumeral joint decoupling in RCT limbs."

Journal • Preclinical • Inflammation • Rheumatology

Vitexin inhibits pain and itch behavior via modulating TRPV4 activity in mice. (PubMed, Biomed Pharmacother) - "Administration of MJS decreased the pruritus response induced by histamine, C48/80, chloroquine and BAM8-22 within 30 min. MJS reduced scratching bouts and lessened the wiping reaction of mice under TRPV4 activation by GSK101 (10 µg/5 μl)...An H receptor antagonist-chlorpheniramine (CLP, 400 mg/kg)-and a TRPV4 antagonist-HC067047 (250 ng/kg), exhibited similar effects to those of MJS...MJS did not inhibit the expression of TRPV4 in the dorsal root ganglion neurons at L2-L3 in AEW mice. These results indicate that the analgesic and anti-pruritic effects of MJS in acute and chronic pain and itching, as well as itching caused by TRPV4 activation, could be attributed to the TRPV4 pathway modulation."

Journal • Preclinical • Dermatology • Pain • Pruritus • TRPV4

Silencing of TRPV4-expressing sensory neurons attenuates temporomandibular disorders pain. (PubMed, Mol Pain) - "Moreover, co-administration of QX-314 and GSK101 into the TG significantly attenuated pain in mouse models of temporomandibular joint (TMJ) inflammation and masseter muscle injury. Collectively, these results suggest TRPV4-expressing TG neurons represent a potential target for TMD pain."

Journal • Inflammation • Musculoskeletal Diseases • Pain • Rheumatology

Modes of action of lysophospholipids as endogenous activators of the TRPV4 ion channel. (PubMed, J Physiol) - "The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known. TRPV4 is activated by the bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose-dependent manner, both in a primary and a heterologous expression system. Activation of TRPV4 by LPA18:1 requires residues in the N- and C-termini of the ion channel. Single-channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single-channel amplitude. Distinct single-channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions."

Journal • Immunology • Inflammation

Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc. (PubMed, FASEB J) - "Activating TRPV4 with the agonist GSK101 resulted in a Ca flux propagating across the cells within the IVD...These results indicate TRPV4 plays an important role in both short- and long-term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load-induced IVD degeneration."

Journal • Fibrosis • Immunology • Inflammation • IL6