儿科临床前测试计划对 Notch 抑制剂 PF-03084014 进行初步测试（第 1 阶段）。
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.
机构信息
Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
出版信息
Pediatr Blood Cancer. 2014 Aug;61(8):1493-6. doi: 10.1002/pbc.25026. Epub 2014 Mar 24.
Abstract
PF-03084014, a γ-secretase inhibitor, was tested against the PPTP in vitro cell line panel (1.0 nM to 10 μM) and against the in vivo xenograft panels (administered orally twice daily on Days 1-7 and 15-21). PF-03084014 demonstrated limited in vitro activity, with no cell line achieving ≥50% inhibition. PF-03084014 induced significant differences in EFS distribution in 14 of 35 (40%) solid tumor xenografts, and 1 of 9 ALL xenografts (which lacked a NOTCH1 mutation), but objective responses were not observed. PF-03084014 demonstrated limited single agent activity in vitro and in vivo against the pediatric preclinical models studied.
摘要
PF-03084014，一种γ-分泌酶抑制剂，在体外细胞系（1.0 nM 至 10 μM）和体内异种移植（每天口服两次，第 1-7 天和第 15-21 天）中进行了测试。PF-03084014在体外表现出有限的活性，没有一个细胞系的抑制率达到≥50%。PF-03084014在 35 个实体瘤异种移植中的 14 个（40%）和 9 个 ALL 异种移植中的 1 个（没有 NOTCH1 突变）中诱导了 EFS 分布的显著差异，但未观察到客观反应。PF-03084014在体外和体内对所研究的儿科临床前模型表现出有限的单药活性。
相似文献
1
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.儿科临床前测试计划对 Notch 抑制剂 PF-03084014 进行初步测试（第 1 阶段）。
Pediatr Blood Cancer. 2014 Aug;61(8):1493-6. doi: 10.1002/pbc.25026. Epub 2014 Mar 24.
2
Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP).儿科临床前试验计划（PPTP）对极光激酶 A 抑制剂 MLN8237 的初步测试。
Pediatr Blood Cancer. 2010 Jul 15;55(1):26-34. doi: 10.1002/pbc.22430.
3
Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program.小儿临床前测试项目对VEGFR抑制剂AZD2171进行的初步测试。
Pediatr Blood Cancer. 2008 Mar;50(3):581-7. doi: 10.1002/pbc.21232.
4
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.γ-分泌酶抑制剂 PF-03084014 在乳腺癌模型中的生物标志物和药理学评价。
Clin Cancer Res. 2012 Sep 15;18(18):5008-19. doi: 10.1158/1078-0432.CCR-12-1379. Epub 2012 Jul 17.
5
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.评估选择性 γ-分泌酶抑制剂 PF-03084014 的抗肿瘤疗效和胃肠道安全性，以指导最佳临床试验设计。
Mol Cancer Ther. 2010 Jun;9(6):1618-28. doi: 10.1158/1535-7163.MCT-10-0034. Epub 2010 Jun 8.
6
Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program.儿科临床前试验计划对 Polo 样激酶抑制剂 BI 6727（volasertib）进行初步测试（第一阶段）。
Pediatr Blood Cancer. 2014 Jan;61(1):158-64. doi: 10.1002/pbc.24616. Epub 2013 Aug 19.
7
Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the Pediatric Preclinical Testing Program.儿科临床前试验计划对 Hsp90 抑制剂 ganetespib 的初步测试（第 1 阶段）。
Pediatr Blood Cancer. 2013 Jul;60(7):E42-5. doi: 10.1002/pbc.24451. Epub 2013 Jan 9.
8
Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program.儿科临床前试验计划对新型 mTOR 激酶抑制剂 MLN0128 的初步测试（第一阶段）。
Pediatr Blood Cancer. 2014 Aug;61(8):1486-9. doi: 10.1002/pbc.24989. Epub 2014 Feb 20.
9
Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.与XPO1/CRM1抑制剂塞利尼索（KPT-330）反应相关的药效学和基因组标志物：来自儿科临床前测试项目的报告。
Pediatr Blood Cancer. 2016 Feb;63(2):276-86. doi: 10.1002/pbc.25727. Epub 2015 Sep 23.
10
Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.儿科临床前试验计划用新型黏着斑激酶（FAK）抑制剂 VS-4718 对儿科肿瘤模型进行初步测试。
Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26304. Epub 2016 Oct 27.
引用本文的文献
1
HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.HepaCAM 通过下调 Notch 信号通路抑制去势抵抗性前列腺癌细胞的恶性行为，PF-3084014（一种 γ-分泌酶抑制剂）部分逆转了难治性前列腺癌对多西他赛和恩扎卢胺的体外耐药性。
Int J Oncol. 2018 Jul;53(1):99-112. doi: 10.3892/ijo.2018.4370. Epub 2018 Apr 12.
2
A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program.儿科临床前试验计划评估的针对小儿急性淋巴细胞白血病的新药物的综述。
Leukemia. 2016 Nov;30(11):2133-2141. doi: 10.1038/leu.2016.192. Epub 2016 Jul 15.
3
Molecular profiling of childhood cancer: Biomarkers and novel therapies.儿童癌症的分子剖析：生物标志物与新型疗法。
BBA Clin. 2014 Jun 28;1:59-77. doi: 10.1016/j.bbacli.2014.06.003. eCollection 2014 Jun.
4
Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.破坏NOTCH可减缓弥漫性固有桥脑胶质瘤的生长，增强放射敏感性，并显示出与溴结构域抑制联合使用的疗效。
J Neuropathol Exp Neurol. 2015 Aug;74(8):778-90. doi: 10.1097/NEN.0000000000000216.
5
New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers.乳腺癌的新型靶向治疗：聚焦肿瘤微环境信号与化疗耐药性乳腺癌
World J Clin Cases. 2014 Dec 16;2(12):769-86. doi: 10.12998/wjcc.v2.i12.769.
本文引用的文献
1
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.γ-分泌酶抑制剂 PF-03084014 在乳腺癌模型中的生物标志物和药理学评价。
Clin Cancer Res. 2012 Sep 15;18(18):5008-19. doi: 10.1158/1078-0432.CCR-12-1379. Epub 2012 Jul 17.
2
Targeting the Notch pathway: twists and turns on the road to rational therapeutics.靶向Notch信号通路：通往合理治疗之路的曲折历程
J Clin Oncol. 2012 Jul 1;30(19):2418-20. doi: 10.1200/JCO.2012.42.0992. Epub 2012 May 14.
3
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.γ-分泌酶抑制剂 PF-03084014 联合糖皮质激素在 T 细胞急性淋巴细胞白血病中的临床前分析。
Mol Cancer Ther. 2012 Jul;11(7):1565-75. doi: 10.1158/1535-7163.MCT-11-0938. Epub 2012 Apr 13.
4
The double-edged sword of Notch signaling in cancer. Notch 信号通路在癌症中的双刃剑作用。
Semin Cell Dev Biol. 2012 Jun;23(4):458-64. doi: 10.1016/j.semcdb.2012.01.017. Epub 2012 Jan 30.
5
Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling.RO4929097 是一种针对 Notch 信号的 γ-分泌酶抑制剂，儿科临床前测试计划进行了初步测试（第 1 阶段）。
Pediatr Blood Cancer. 2012 May;58(5):815-8. doi: 10.1002/pbc.23290. Epub 2011 Aug 16.
6
Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion.γ-分泌酶抑制剂治疗促进 VEGF-A 驱动的血管生长和血管渗漏，但破坏新血管灌注。
PLoS One. 2011 Apr 14;6(4):e18709. doi: 10.1371/journal.pone.0018709.
7
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.新型四氢萘氨基咪唑类γ-分泌酶抑制剂的设计、合成及体内评价：PF-3084014 的发现。
Bioorg Med Chem Lett. 2011 May 1;21(9):2637-40. doi: 10.1016/j.bmcl.2010.12.118. Epub 2010 Dec 30.
8
Notch pathway inhibition significantly reduces rhabdomyosarcoma invasiveness and mobility in vitro.Notch 通路抑制显著降低横纹肌肉瘤的体外侵袭性和迁移能力。
Clin Cancer Res. 2011 Feb 1;17(3):505-13. doi: 10.1158/1078-0432.CCR-10-0166. Epub 2010 Dec 21.
9
Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.Notch信号通路的抑制可阻断胶质母细胞瘤细胞系和肿瘤神经球的生长。
Genes Cancer. 2010 Aug;1(8):822-35. doi: 10.1177/1947601910383564.
10
Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies.Notch 信号通路在 T 细胞淋巴母细胞白血病/淋巴瘤和其他血液系统恶性肿瘤中的作用。
J Pathol. 2011 Jan;223(2):262-73. doi: 10.1002/path.2789. Epub 2010 Oct 21.
Zotero 插件