更新于：2024-11-01

TAF1B x ASTE1 x TGFBR2

更新于：2024-11-01

基本信息

关联

项与 TAF1B x ASTE1 x TGFBR2 相关的药物

FMPV-3

靶点

ASTE1 x TAF1B x TGFBR2

作用机制

ASTE1调节剂 [+2]

在研机构

Hubro Therapeutics AS

原研机构

Hubro Therapeutics AS

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TAF1B x ASTE1 x TGFBR2 相关的临床结果

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100 项与 TAF1B x ASTE1 x TGFBR2 相关的转化医学

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0 项与 TAF1B x ASTE1 x TGFBR2 相关的专利（医药）

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项与 TAF1B x ASTE1 x TGFBR2 相关的文献（医药）

2013-03-01·Scandinavian Journal of Gastroenterology4区 · 医学

Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicatesSEC63as potential target gene in hepatocarcinogenesis

4区 · 医学

Article

作者: Roman Müllenbach ; Rainer Grobholz ; Susanne N Weber ; Markus Casper ; Vincent Zimmer ; Matthias Kloor ; Frank Lammert

OBJECTIVELynch syndrome is a cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes with microsatellite instability (MSI) as its molecular hallmark. Hepatocellular carcinoma (HCC) has not been considered part of the tumor spectrum. The aim was to provide a detailed molecular characterization of an HCC associated with Lynch Syndrome (Muir-Torre variant).MATERIALS AND METHODSHCC samples were analyzed for MSI, MMR protein expression and coding microsatellite instability (cMSI). Since cMSI also affected SEC63 coding for an endoplasmic reticulum membrane protein with implications for intracellular protein translocation, its impact on hepatocyte growth control was assessed in an established short-term model. Recombinant inbred mouse lines (BXD) showing different basal SEC63 expression levels were treated with the chemocarcinogen diethylnitrosamine (DEN) intraperitoneally. Proliferation and apoptosis of hepatocytes were determined after 48 h using Ki67 and TUNEL assays.RESULTSThe HCC was high-grade microsatellite unstable with loss of MSH2 expression. cMSI was detected in four genes (ASTE1, SEC63, TAF1B, TGFBR2). However, only TGFBR2 is known to be involved in hepatocarcinogenesis. When investigating the impact of SEC63 expression on hepatocyte growth control in the murine model, low hepatic expression correlated significantly (p < 0.05) with a decrease in apoptosis and increased proliferative activity.CONCLUSIONSFor the first time, an HCC with characteristic molecular features of association with Lynch syndrome is described. The pro-carcinogenic growth behavior of hepatocytes with low SEC63 expression in the murine model indicates a potential role for SEC63 in hepatocarcinogenesis in general, but this needs further functional validation.

2009-09-01·Modern Pathology1区 · 医学

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

1区 · 医学

Article

作者: Jean-Baptiste Latouche ; Frédéric Di Fiore ; Richard Sesboüé ; Thierry Frébourg ; Jean-Christophe Sabourin ; Michèle Laurent ; David Tougeron ; Jacques Mauillon ; Emilie Fauquembergue ; Pascaline Berthet ; Mario Tosi ; Florence Le Pessot ; Pierre Michel ; Alexandre Rouquette

Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3+ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.