Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia.
Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia.
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在急性髓样白血病的临床前模型中，将BH3摄影作用靶向Bcl-2和Mcl1具有有效的活性。
DOI：
10.1038/s41375-018-0261-3
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发表时间：
2019-04
期刊：
影响因子：
11.4
通讯作者：
Wei AH
中科院分区：
文献类型：
--
作者：
Moujalled DM;Pomilio G;Ghiurau C;Ivey A;Salmon J;Rijal S;Macraild S;Zhang L;Teh TC;Tiong IS;Lan P;Chanrion M;Claperon A;Rocchetti F;Zichi A;Kraus-Berthier L;Wang Y;Halilovic E;Morris E;Colland F;Segal D;Huang D;Roberts AW;Maragno AL;Lessene G;Geneste O;Wei AH
改善急性髓性白血病（AML）的预后仍然是一个重大的临床挑战。促存活BCL-2家族成员的过表达使得转化细胞对细胞毒性药物具有抗性是癌症中的常见主题。当与低剂量化疗或低甲基化剂联合使用时，用BH 3模拟物维奈托克靶向BCL-2在AML中是有效的。我们现在报告了一种新型BCL-2抑制剂S55746的临床前抗白血病疗效，该抑制剂与MCL 1抑制剂S63845组合显示出协同促凋亡活性。该组合的活性是半胱天冬酶和BAX/巴克依赖性的，上级于与标准细胞毒性AML药物的组合，并且对广泛的低风险基因型具有活性，包括来自化疗耐药AML患者的原始样品。与正常造血祖细胞相比，共靶向BCL-2和MCL 1对白血病更有效，这表明了活性的治疗窗口。最后，S55746联合S63845延长了AML异种移植模型的存活时间，并抑制了移植小鼠骨髓中的患者源性白血病细胞，但不抑制正常造血细胞。总之，双重BH 3-模拟方法在不同的人AML模型中是可行的、高度协同的和有活性的。这种方法具有快速抑制白血病的强大临床潜力，与化疗相比，对正常造血前体细胞的毒性降低。
Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.
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DOI：
10.1056/nejmoa1513257
发表时间：
2016-01-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Roberts AW;Davids MS;Pagel JM;Kahl BS;Puvvada SD;Gerecitano JF;Kipps TJ;Anderson MA;Brown JR;Gressick L;Wong S;Dunbar M;Zhu M;Desai MB;Cerri E;Heitner Enschede S;Humerickhouse RA;Wierda WG;Seymour JF
通讯作者：
Seymour JF
影响因子：
--
作者：
Casara P;Davidson J;Claperon A;Le Toumelin-Braizat G;Vogler M;Bruno A;Chanrion M;Lysiak-Auvity G;Le Diguarher T;Starck JB;Chen I;Whitehead N;Graham C;Matassova N;Dokurno P;Pedder C;Wang Y;Qiu S;Girard AM;Schneider E;Gravé F;Studeny A;Guasconi G;Rocchetti F;Maïga S;Henlin JM;Colland F;Kraus-Berthier L;Le Gouill S;Dyer MJS;Hubbard R;Wood M;Amiot M;Cohen GM;Hickman JA;Morris E;Murray J;Geneste O
通讯作者：
Geneste O
影响因子：
64.5
作者：
Mason, Kylie D.;Carpinelli, Marina R.;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
影响因子：
56.9
作者：
Opferman, JT;Iwasaki, H;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.