An orally available cancer drug AZD6738 prevents type 1 diabetes.
An orally available cancer drug AZD6738 prevents type 1 diabetes.
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DOI：
10.3389/fimmu.2023.1290058
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
1型糖尿病（T1D）影响着300万美国人，每天有80名新患者被诊断出来。T1D目前是无法治愈的，迫切需要开发额外的候选药物来实现对T1D的预防。AZD6738 （ATRi）是一种口服药物，目前正处于各种癌症的I期和II期临床试验中，作为预防T1D的新候选药物。基于先前报道的ATRi在快速增殖的T细胞中诱导细胞死亡的发现，我们假设这种药物会特异性地影响自身抗原激活的糖尿病源性T细胞。如果不加以控制，这些细胞可能会导致胰腺β细胞的破坏，从而导致T1D的发展。这项工作表明，增加ATRi治疗的持续时间可以延长对T1D发病的保护。值得注意的是，在稳健的过继性转移小鼠模型中，5周的ATRi治疗可预防T1D。此外，接受5周ATRi治疗的动物的脾细胞没有转移免疫介导的糖尿病，而对照动物的脾细胞在10天内转移了疾病。这项研究表明，ATRi通过诱导DNA损伤，特异性诱导自身抗原激活的、高度增殖的糖尿病源性T细胞死亡，从而抑制IFNγ的产生和增殖，从而预防T1D。这些发现支持将ATRi重新用于T1D预防的考虑。
Type 1 diabetes (T1D) affects three million Americans, with 80 new people diagnosed each day. T1D is currently uncurable and there is an urgent need to develop additional drug candidates to achieve the prevention of T1D. We propose AZD6738 (ATRi), an orally available drug currently in phases I and II of clinical trials for various cancers, as a novel candidate to prevent T1D. Based on previously reported findings of ATRi inducing cell death in rapidly proliferating T cells, we hypothesized that this drug would specifically affect self-antigen activated diabetogenic T cells. These cells, if left unchecked, could otherwise lead to the destruction of pancreatic β cells, contributing to the development of T1D. This work demonstrates that increasing the duration of ATRi treatment provides extended protection against T1D onset. Remarkably, 5-week ATRi treatment prevented T1D in a robust adoptive transfer mouse model. Furthermore, the splenocytes of animals that received 5-week ATRi treatment did not transfer immune-mediated diabetes, while the splenocytes from control animal transferred the disease in 10 days. This work shows that ATRi prevents T1D by specifically inducing cell death in self-antigen activated, highly proliferative diabetogenic T cells through the induction of DNA damage, resulting in the inhibition of IFNγ production and proliferation. These findings support the consideration of repurposing ATRi for T1D prevention.
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影响因子：
16.6
作者：
Moiseeva T;Hood B;Schamus S;O'Connor MJ;Conrads TP;Bakkenist CJ
通讯作者：
Bakkenist CJ
影响因子：
8
作者：
Vendetti, Frank P.;Pandya, Pinakin;Clump, David A.;Schamus-Haynes, Sandra;Tavakoli, Meysam;diMayorca, Maria;Islam, Naveed M.;Chang, Jina;Delgoffe, Greg M.;Beumer, Jan H.;Bakkenist, Christopher J.
通讯作者：
Bakkenist, Christopher J.
影响因子：
7.3
作者：
Foote, Kevin M.;Nissink, J. Willem M.;Jewsbury, Philip J.
通讯作者：
Jewsbury, Philip J.
DOI：
10.2337/cd23-0033
发表时间：
2023-01-01
期刊：
Clinical diabetes : a publication of the American Diabetes Association
影响因子：
--
作者：
Goldman, Jennifer D;Choi, Hailey
通讯作者：
Choi, Hailey
DOI：
10.1158/1078-0432.ccr-21-0251
发表时间：
2021-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kim ST;Smith SA;Mortimer P;Loembé AB;Cho H;Kim KM;Smith C;Willis S;Irurzun-Arana I;Berges A;Hong JY;Park SH;Park JO;Park YS;Lim HY;Kang WK;Kozarewa I;Pierce AJ;Dean E;Lee J
通讯作者：
Lee J