Jue Toni Rose, Nozue Kyoko, Lester Ashleigh J, Joshi Swapna, Schroder Lisette B W, Whittaker Shane P, Nixdorf Sheri, Rapkins Robert W, Khasraw Mustafa, McDonald Kerrie L
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Kensington, Australia.
Royal North Shore Hospital, St Leonards, NSW, Australia.
J Transl Med. 2017 Mar 17;15(1):61. doi: 10.1186/s12967-017-1164-1.
The O -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.
The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors.
The combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only.
Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.
胶质母细胞瘤（GBM）患者的O-甲基鸟嘌呤甲基转移酶（MGMT）基因常未发生甲基化，这使得他们对手术联合同步放疗（RT）和替莫唑胺的标准治疗方案无反应。在此，我们研究添加聚（ADP-核糖）聚合酶（PARP）抑制剂维利帕尼至放疗中治疗MGMT未甲基化GBM的疗效。
在一组源自MGMT未甲基化肿瘤的GBM患者的患者来源细胞系（PDCLs）和患者来源异种移植（PDX）模型上，测试维利帕尼（ABT-888）（一种强效且口服生物可利用的抑制剂）联合RT对PARP的抑制作用。
维利帕尼与RT的联合抑制了大多数测试PDCLs中的集落形成。PDCL RN1显示同源修复蛋白Mre11水平显著降低，且通过增加的凋亡和减少的集落形成来衡量，其对PARP抑制的反应增强。在MGMT未甲基化GBM的一个PDX中，口服维利帕尼（12.5mg/kg，在28天治疗周期内每日两次，共5天）联合全脑RT（4Gy）可诱导凋亡（Tunel染色）并减少细胞增殖（Ki67染色）。与仅接受RT或仅接受维利帕尼治疗相比，联合治疗的PDX存活时间显著延长。
我们的结果证明了在多个水平靶向PARP的临床前疗效，并为治疗MGMT未甲基化GBM提供了一种新方法。
