更新于：2024-11-01

ASTE1

更新于：2024-11-01

基本信息

别名

ASTE1、asteroid homolog 1、HT001

+ [1]

简介

Possible role in EGF receptor signaling.

关联

项与 ASTE1 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

FMPV-2

靶点

ASTE1

作用机制

ASTE1调节剂 [+1]

在研机构

Hubro Therapeutics AS

原研机构

Hubro Therapeutics AS

在研适应症

子宫内膜癌

非在研适应症

结直肠癌

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 ASTE1 相关的临床结果

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100 项与 ASTE1 相关的转化医学

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0 项与 ASTE1 相关的专利（医药）

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项与 ASTE1 相关的文献（医药）

2021-08-01·Nature Cell Biology1区 · 生物学

ASTE1 cutting to block DNA end resection

1区 · 生物学

Article

作者: He, Yizhou Joseph ; Chowdhury, Dipanjan

Cells rely on two main pathways to repair DNA lesions, homologous recombination and non-homologous end-joining, and how they decide to use one machinery over the other is not clear.A recent study identifies ASTE1 as a regulator controlling pathway choice.

2021-08-01·Nature Cell Biology1区 · 生物学

ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection

1区 · 生物学

Article

作者: Zhou, Qin ; Liu, Yilun ; Guo, Guijie ; Hu, Qi ; Kim, Wootae ; Gao, Huanyao ; Gao, Ming ; Zhang, Yong ; Zhang, Chao ; Yuan, Jian ; Luo, Kuntian ; Tu, Xinyi ; Deng, Min ; Yin, Ping ; Lou, Zhenkun ; Liu, Chao ; Chen, Shih-Hsun ; Qin, Sisi ; Qin, Bo ; Zhao, Fei ; Kloeber, Jake A ; Nowsheen, Somaira ; Chen, Yuping ; Huang, Jinzhou

The shieldin complex functions as the downstream effector of 53BP1-RIF1 to promote DNA double-strand break end-joining by restricting end resection. The SHLD2 subunit binds to single-stranded DNA ends and blocks end resection through OB-fold domains. Besides blocking end resection, it is unclear how the shieldin complex processes SHLD2-bound single-stranded DNA and promotes non-homologous end-joining. Here, we identify a downstream effector of the shieldin complex, ASTE1, as a structure-specific DNA endonuclease that specifically cleaves single-stranded DNA and 3' overhang DNA. ASTE1 localizes to DNA damage sites in a shieldin-dependent manner. Loss of ASTE1 impairs non-homologous end-joining, leads to hyper-resection and causes defective immunoglobulin class switch recombination. ASTE1 deficiency also causes resistance to poly(ADP-ribose) polymerase inhibitors in BRCA1-deficient cells owing to restoration of homologous recombination. These findings suggest that ASTE1-mediated 3' single-stranded DNA end cleavage contributes to the control of DSB repair choice by 53BP1, RIF1 and shieldin.

2020-09-01·Clinical Cancer Research

A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial

Article

作者: Al-Batran, Salah-Eddin ; Pauligk, Claudia ; Reuschenbach, Miriam ; Kloor, Matthias ; Rafiyan, Mohammad-Reza ; Karbach, Julia ; Jäger, Elke ; Tariverdian, Mirjam ; von Knebel Doeberitz, Magnus

AbstractPurpose:DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx).Patients and Methods:The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients).Results:Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months.Conclusions:FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.