Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma.
Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma.
复制标题
在超突变的内在庞然神经胶质瘤中的治疗性HDAC抑制作用。
DOI：
10.1016/j.neo.2023.100921
复制
发表时间：
2023-09
期刊：
影响因子：
4.8
通讯作者：
Vitanza, Nicholas A.
中科院分区：
文献类型：
--
作者：
Noll, Alyssa;Myers, Carrie;Biery, Matthew C.;Meechan, Michael;Tahiri, Sophie;Rajendran, Asmitha;Berens, Michael E.;Paine, Danyelle;Byron, Sara;Zhang, Jiaming;Winter, Conrad;Pakiam, Fiona;Leary, Sarah E. S.;Cole, Bonnie L.;Jackson, Evangeline R.;Dun, Matthew D.;Foster, Jessica B.;Evans, Myron K.;Pattwell, Siobhan S.;Olsona, James M.;Vitanza, Nicholas A.
关键词：
错配修复缺陷综合征（CMMRD）是一种癌症易感综合征，与儿童高级别胶质瘤的高突变发生相关，且预后不良。虽然已有关于弥漫性内生性脑桥胶质瘤（DIPG）的治疗性组蛋白去乙酰化酶（HDAC）抑制的报道，但在此我们使用一种具有临床相关性的活检来源的高突变DIPG模型（PBT - 24FH）以及一个CRISPR - Cas9诱导的基因模型来评估HDAC抑制对高突变DIPG的疗效。我们在体外对PBT - 24FH细胞进行了一组HDAC抑制剂（HDACis）敏感性筛选，确定了两种与低纳摩尔半数抑制浓度（IC50）相关的HDACis，即quisinostat（27 nM）和romidepsin（2 nM）。在体内，quisinostat被证明更有效，在PBT - 24FH侧翼肿瘤模型中诱导了近乎完全的肿瘤消退。RNA测序显示quisinostat驱动基因表达发生显著变化，包括神经和促炎基因的上调。为了验证所观察到的quisinostat在体内对其他高突变DIPG模型的效力，我们在基因诱导的错配修复（MMR）缺陷的DIPG侧翼肿瘤中测试了quisinostat，结果表明MMR功能缺失会增加体内对quisinostat的敏感性。在此，我们确立了quisinostat对高突变DIPG的临床前疗效，支持对具有临床转化潜力的儿童高突变癌症的表观遗传学靶向进行进一步研究。这些发现支持对HDAC抑制剂针对脑桥高级别胶质瘤（不仅仅是那些具有组蛋白突变的）以及其他高突变中枢神经系统肿瘤进行进一步研究。
Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
登录
查看更多内容
DOI：
10.1016/j.trsl.2017.06.013
发表时间：
2017-11
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Rogawski DS;Vitanza NA;Gauthier AC;Ramaswamy V;Koschmann C
通讯作者：
Koschmann C
种系DNA复制修复缺乏儿童对PD-1抑制反应的基因组预测指标。
影响因子：
82.9
作者：
Das A;Sudhaman S;Morgenstern D;Coblentz A;Chung J;Stone SC;Alsafwani N;Liu ZA;Karsaneh OAA;Soleimani S;Ladany H;Chen D;Zatzman M;Cabric V;Nobre L;Bianchi V;Edwards M;Sambira Nahum LC;Ercan AB;Nabbi A;Constantini S;Dvir R;Yalon-Oren M;Campino GA;Caspi S;Larouche V;Reddy A;Osborn M;Mason G;Lindhorst S;Bronsema A;Magimairajan V;Opocher E;De Mola RL;Sabel M;Frojd C;Sumerauer D;Samuel D;Cole K;Chiaravalli S;Massimino M;Tomboc P;Ziegler DS;George B;Van Damme A;Hijiya N;Gass D;McGee RB;Mordechai O;Bowers DC;Laetsch TW;Lossos A;Blumenthal DT;Sarosiek T;Yen LY;Knipstein J;Bendel A;Hoffman LM;Luna-Fineman S;Zimmermann S;Scheers I;Nichols KE;Zapotocky M;Hansford JR;Maris JM;Dirks P;Taylor MD;Kulkarni AV;Shroff M;Tsang DS;Villani A;Xu W;Aronson M;Durno C;Shlien A;Malkin D;Getz G;Maruvka YE;Ohashi PS;Hawkins C;Pugh TJ;Bouffet E;Tabori U
通讯作者：
Tabori U
影响因子：
15.9
作者：
通讯作者：
--
影响因子：
15.9
作者：
Ostrom, Quinn T.;Gittleman, Haley;Barnholtz-Sloan, Jill S.
通讯作者：
Barnholtz-Sloan, Jill S.
影响因子：
82.9
作者：
Grasso CS;Tang Y;Truffaux N;Berlow NE;Liu L;Debily MA;Quist MJ;Davis LE;Huang EC;Woo PJ;Ponnuswami A;Chen S;Johung TB;Sun W;Kogiso M;Du Y;Qi L;Huang Y;Hütt-Cabezas M;Warren KE;Le Dret L;Meltzer PS;Mao H;Quezado M;van Vuurden DG;Abraham J;Fouladi M;Svalina MN;Wang N;Hawkins C;Nazarian J;Alonso MM;Raabe EH;Hulleman E;Spellman PT;Li XN;Keller C;Pal R;Grill J;Monje M
通讯作者：
Monje M