Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.
Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.
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DOI：
10.18632/oncotarget.20936
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发表时间：
2017-10-20
期刊：
影响因子：
--
通讯作者：
Bristow RG
中科院分区：
文献类型：
--
作者：
Borst GR;Kumareswaran R;Yücel H;Telli S;Do T;McKee T;Zafarana G;Jonkers J;Verheij M;O'Connor MJ;Rottenberg S;Bristow RG
临床试验正在研究PARP-1抑制剂奥拉帕尼与化疗和放疗联合治疗多种癌症的益处，提高奥拉帕尼的治疗率可能来自其通过靶向同源重组缺陷、缺氧肿瘤克隆原和/或增加肿瘤相关血管舒张以改善氧合来改变肿瘤微环境的能力。在本文中，我们使用基因工程小鼠p53−/−同基因乳腺癌模型研究了长期新辅助暴露于奥拉帕尼对肿瘤微环境的影响，该模型精通同源定向DNA修复。我们观察到在12 Gy的辐射剂量之前用奥拉帕尼50 mg/kg bid奥拉帕尼预处理7天结束48小时后体内生长延迟增加和离体克隆形成存活减少。这种增加的体内放射反应与减少缺氧分数。这项研究表明，如果在放射治疗开始之前，在纯新辅助治疗环境中给予奥拉帕尼以改变肿瘤微环境，则可以改善患者的放射反应，毒性有限。因此，在治疗窗内可以实现显著的增益，并且需要临床研究来确认该临床前数据。
Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53−/− syngeneic breast cancer model, which is proficient in homology-directed DNA repair. We observed increased in vivo growth delay and decreased ex vivo clonogenic survival following pre-treatment with olaparib 50 mg/kg bid Olaparib for 7 days ending 48 hours prior to a radiation dose of 12Gy. This increased in vivo radioresponse was associated with a decreased hypoxic fraction. This study suggests that the radiation response in patients can be improved with limited toxicity if olaparib is given in a purely neoadjuvant setting to modify the tumor microenviroment prior to the start of the radiotherapy treatment. Consequently a significant gain can be achieved in therapeutic window and clinical studies are needed to confirm this preclinical data.
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基于肿瘤微环境的癌细胞杀伤的背景综合致死率。
影响因子：
11.2
作者：
Chan N;Pires IM;Bencokova Z;Coackley C;Luoto KR;Bhogal N;Lakshman M;Gottipati P;Oliver FJ;Helleday T;Hammond EM;Bristow RG
通讯作者：
Bristow RG
影响因子：
--
作者：
Caldini, Riccardo;Fanti, Elena;Chevanne, Marta
通讯作者：
Chevanne, Marta
影响因子：
8.4
作者：
Tentori, Lucio;Lacal, Pedro Miguel;Graziani, Grazia
通讯作者：
Graziani, Grazia
影响因子：
4.1
作者：
Al-Husein, Belal;Abdalla, Maha;Trepte, Morgan;DeRemer, David L.;Somanath, Payaningal R.
通讯作者：
Somanath, Payaningal R.
DOI：
10.1073/pnas.0806092105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Rottenberg, Sven;Jaspers, Janneke E.;Jonkers, Jos
通讯作者：
Jonkers, Jos