Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma.
Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma.
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DOI：
10.1016/j.tranon.2022.101368
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发表时间：
2022-04
影响因子：
5
通讯作者：
Li XN
中科院分区：
文献类型：
--
作者：
Kogiso M;Qi L;Du Y;Braun FK;Zhang H;Huang LF;Guo L;Huang Y;Teo WY;Lindsay H;Zhao S;Injac SG;Liu Z;Mehta V;Tran D;Li F;Baxter PA;Su JM;Perlaky L;Parsons DW;Chintagumpala M;Adesina A;Song Y;Li XN
一对新型的伴随IDH1-R132H/R132C突变的神经胶质瘤的原位PDX模型。
具有标准疗法的新型突变IDH1I（SY-435）提高了强大的治疗效率。
H3K4/K9甲基化/mtDNA编码的分子培养基的抗肿瘤活性。
发现MyO1F，CTC1和BCl9是介导SYC-435抗性的新基因。
WHO II/III级星形胶质细胞瘤，少突胶质瘤或继发性胶质母细胞瘤的临床结局仍然很差。携带R132H的原位神经胶质瘤特征模型（IC-BT142AOA）突变和我们新建立的原位患者衍生的Xenographic（PDX）模型的复发性偏型少聚细胞瘤（IC-V0914AOA）轴承R132C突变，除了抑制IDH1 IDH1突变的plumant in IDH1突变。酰胺 +分离辐射）通过还原H3K4/H3K9甲基化和表达来介导线粒体DNA（mtDNA）编织的分子。 SYC-435与标准疗法和确定了一组新的基因，应优先考虑将来的研究以克服SYC-435抗性。
A novel pair of orthotopic PDX models of glioma bearing IDH1-R132H/R132C mutations. New mutant IDH1i (SY-435) with standard therapy led to strong therapeutic efficacy. H3K4/K9 methylation/mtDNA-encoded molecules mediate anti-tumor activity of SYC-435. Discovered MYO1F, CTC1 and BCL9 as novel genes that mediated SYC-435 resistance. Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance.
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影响因子：
4.6
作者：
Kopinja J;Sevilla RS;Levitan D;Dai D;Vanko A;Spooner E;Ware C;Forget R;Hu K;Kral A;Spacciapoli P;Kennan R;Jayaraman L;Pucci V;Perera S;Zhang W;Fischer C;Lam MH
通讯作者：
Lam MH
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Liu Z;Yao Y;Kogiso M;Zheng B;Deng L;Qiu JJ;Dong S;Lv H;Gallo JM;Li XN;Song Y
通讯作者：
Song Y
通过双重抑制NAD+生物合成和碱基切除修复，克服胶质母细胞瘤中替莫唑胺的耐药性。
影响因子：
11.2
作者：
Goellner EM;Grimme B;Brown AR;Lin YC;Wang XH;Sugrue KF;Mitchell L;Trivedi RN;Tang JB;Sobol RW
通讯作者：
Sobol RW
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW