Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors.
Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors.
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热休克蛋白90（HSP90）抑制剂ONALESPIB（AT13387）的I期研究每天在晚期实体瘤患者中每周连续2天给药。
DOI：
10.1007/s10637-015-0255-1
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发表时间：
2015-08
影响因子：
3.4
通讯作者：
Kummar S
中科院分区：
文献类型：
--
作者：
Do K;Speranza G;Chang LC;Polley EC;Bishop R;Zhu W;Trepel JB;Lee S;Lee MJ;Kinders RJ;Phillips L;Collins J;Lyons J;Jeong W;Antony R;Chen AP;Neckers L;Doroshow JH;Kummar S
Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m2/dose and a standard 3+3 dose escalation design for dose level 4 (120 mg/m2/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m2/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T½ ~8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.
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影响因子：
11.5
作者：
Shapiro, Geoffrey I.;Kwak, Eunice;Mahadevan, Daruka
通讯作者：
Mahadevan, Daruka
AT13387对HSP90的抑制作用延迟了对BRAF抑制剂的抗性，并克服了黑色素瘤模型中对双BRAF和MEK抑制的耐药性。
影响因子：
5.7
作者：
Smyth T;Paraiso KHT;Hearn K;Rodriguez-Lopez AM;Munck JM;Haarberg HE;Sondak VK;Thompson NT;Azab M;Lyons JF;Smalley KSM;Wallis NG
通讯作者：
Wallis NG
影响因子：
8.4
作者：
Kummar, Shivaani;Gutierrez, Martin E.;Gardner, Erin R.;Chen, Xiaohong;Figg, William D.;Zajac-Kaye, Maria;Chen, Min;Steinberg, Seth M.;Muir, Christine A.;Yancey, Mary Ann;Horneffer, Yvonne R.;Juwara, Lamin;Melillo, Giovanni;Ivy, S. Percy;Merino, Maria;Neckers, Len;Steeg, Patricia S.;Conley, Barbara A.;Giaccone, Giuseppe;Doroshow, James H.;Murgo, Anthony J.
通讯作者：
Murgo, Anthony J.
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
DOI：
10.1038/nrc2887
发表时间：
2010-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Trepel J;Mollapour M;Giaccone G;Neckers L
通讯作者：
Neckers L