Last update 01 Nov 2024

TWF1

Last update 01 Nov 2024

Basic Info

Synonyms

A6, Protein A6, Protein tyrosine kinase 9

+ [6]

Introduction

Actin-binding protein involved in motile and morphological processes. Inhibits actin polymerization, likely by sequestering G-actin. By capping the barbed ends of filaments, it also regulates motility. Seems to play an important role in clathrin-mediated endocytosis and distribution of endocytic organelles (By similarity).

Drugs associated with TWF1

CN116425869

Patent Mining

Target

TWF1

Mechanism-

Active Org.

Beijing Minhai Biological Technology Co., Ltd.

Originator Org.

Beijing Minhai Biological Technology Co., Ltd.

Active Indication

Infectious Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TWF1

100 Translational Medicine associated with TWF1

0 Patents (Medical) associated with TWF1

473

Literatures (Medical) associated with TWF1

01 Jul 2024·Cancer Communications

Exposure of benzo[a]pyrene induces HCC exosome‐circular RNA to activate lung fibroblasts and trigger organotropic metastasis

Article

Author: Gu, Pengfei ; Ge, Yang ; Jian, Yulun ; Mu, Wei ; Li, Huating ; Zhou, Jinjin ; Jia, Weiping

AbstractBackgroundBenzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P‐induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer‐stroma communications for a toxicologically associated microenvironment.MethodExosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404‐100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre‐education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P‐exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull‐down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the “on‐off” interaction of circRNA‐miRNA pairs. We further developed an adeno‐associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA‐miRNA cascade.ResultsLung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404‐100Bap Exo. In the exosome‐educated in vivo model, fibrosis factors and pro‐inflammatory molecules of are up‐regulated when injected with exosomes. Compared to non‐exposed 7404 cells, circ_0011496 was up‐regulated following B[a]P treatment and was mainly packaged into 7404‐100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR‐486‐5p in recipient fibroblasts. The down‐regulation of miR‐486‐5p converted fibroblast to cancer‐associated fibroblast via regulating the downstream of Twinfilin‐1 (TWF1) and matrix metalloproteinase‐9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer‐stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre‐metastatic niche formation.ConclusionWe demonstrated that B[a]P‐induced tumor exosomes can deliver circ_0011496 to activate miR‐486‐5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.

01 Jun 2024·JHEP Reports

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial

Article

Author: Jäkel, Oliver ; Schirmacher, Peter ; Liermann, Jakob ; Seidensaal, Katharina ; Hörner-Rieber, Juliane ; Habermehl, Daniel ; Chang, De-Hua ; Ben Harrabi, Semi ; Herfarth, Klaus ; Hoffmeister-Wittmann, Paula ; Longerich, Thomas ; Combs, Stephanie E ; Haberer, Thomas ; Dill, Michael T ; Debus, Jürgen ; Springfeld, Christoph ; Ellerbrock, Malte ; Hoegen-Saßmannshausen, Philipp ; Naumann, Patrick ; Mehrabi, Arianeb ; Mielke, Thomas ; Weykamp, Fabian

Background & AimsInoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I.MethodsCIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks.ResultsTwenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression.ConclusionsCIRT of HCC yields excellent local control without dose-limiting toxicity.Impact and implicationsTo date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials.Clinical Trials RegistrationThe study is registered at ClinicalTrials.gov (NCT01167374).

01 Apr 2024·European Journal of Medicinal Chemistry

Discovery of a triphenylamine-based ligand that targets mitochondrial DNA G-quadruplexes and activates the cGAS-STING immunomodulatory pathway

Article

Author: Wang, Xiao-Dong ; Liu, Yong-Si ; Hu, Ming-Hao ; Chen, Meng-Die

Stabilization of G-quadruplex (G4) structures in mitochondria leads to the damage of mitochondrial DNA (mtDNA), making mtDNA G4s a promising target in the field of cancer therapy in recent years. Damaged mtDNA released into the cytosol can stimulate cytosolic DNA-sensing pathways, and cGAS-STING pathway is a typical one with potent immunostimulatory effects. A few small molecule ligands of mtDNA G4s are identified with antitumor efficacy, but little is known about their results and mechanisms on immunomodulation. In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and A6 was determined as the most promising compound. Cellular studies indicated that A6 caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that A6 exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand targeting mtDNA G4s to activate the cGAS-STING immunomodulatory pathway, providing a novel strategy for the future development of mtDNA G4-based antitumor agents.

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TWF1

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