真性红细胞增多症
骨髓纤维化
原发性血小板增多症
鲁索利替尼
骨髓
代理终结点
医学
Janus激酶2
药理学
免疫学
内科学
癌症研究
受体
作者
Gerlinde Wernig,Michael G. Kharas,Rachel Okabe,Sandra Moore,Dena S. Leeman,Dana E. Cullen,Maricel Gozo,Elizabeth M. McDowell,Ross L. Levine,John A. Doukas,Chi H. Mak,Glenn Noronha,Michael C. Martin,Yon Ko,Benjamin R. Lee,Richard Soll,Ayalew Tefferi,John Hood,D. Gary Gilliland
出处
期刊:Blood
[American Society of Hematology]
日期:2007-11-16
被引量:2
标识
DOI:10.1182/blood.v110.11.556.556
摘要
Abstract The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. However, the potential toxicities of JAK2 inhibition in vivo, and identification of appropriate surrogate endpoints for response, are challenges that may limit clinical usefulness in treatment of these relatively indolent diseases. We report efficacy and assessment of surrogate endpoints for response of a small molecule JAK2 inhibitor, TG101348 in a murine model of polycythemia vera. TG101348 is selective for JAK2 with an in vitro IC50 of ∼3 nM that is ∼334 fold more potent than for inhibition of JAK3. TG101348 showed therapeutic efficacy in the murine model of PV that included a statistically significant reduction in hematocrit, normalization of white blood cell count, a dose dependent reduction/elimination of extramedullary hematopoiesis in the spleen and liver, and marked attenuation of myelofibrosis. Consistent with its selective inhibition of JAK2 and not JAK3, there was no significant change in T-cell number in treated animals. These clinical responses correlated with surrogate endpoints for response, including reduction or elimination of JAK2V617F expressing clones based on quantitative genomic PCR, suppression of JAK2V617F positive endogenous erythroid colony growth of JAK2V617F MPD bone marrow, and inhibition of JAK-STAT signal transduction as assessed by phosphoflow cytometry for phosphorylated STAT5. Thus, TG101348 is efficacious in treatment of a murine model of PV, and surrogate endpoints have been identified that may be of value in clinical trials in humans.
科研通智能强力驱动
Strongly Powered by AbleSci AI