Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.
Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.
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DOI：
10.1371/journal.pone.0142612
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Geoerger B
中科院分区：
文献类型：
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作者：
Daudigeos-Dubus E;Le Dret L;Lanvers-Kaminsky C;Bawa O;Opolon P;Vievard A;Villa I;Pagès M;Bosq J;Vassal G;Zopf D;Geoerger B
多激酶抑制剂瑞戈非尼（BAY 73-4506）在成人实体恶性肿瘤（主要是晚期结直肠癌和胃肠道间质瘤）中发挥抗血管生成和抗肿瘤生成活性。我们打算在临床前探索瑞戈非尼单独或与抗癌药物联合治疗儿科实体恶性肿瘤的潜力，以指导儿科开发计划。针对儿童癌症创新疗法（ITCC）小组的33种实体瘤细胞系筛选了对细胞增殖的体外影响，涵盖5种儿科实体恶性肿瘤。瑞格非尼抑制细胞增殖，平均半数最大生长抑制为12.5 μmol/L（范围为0.7 μmol/L至28 μmol/L）。在体内，评价了瑞戈非尼10或30 mg/kg/d单独给药或与放疗、伊立替康或丝裂原活化蛋白激酶激酶（MEK）抑制剂瑞法美替尼联合给药对各种肿瘤类型的抑制作用，包括血小板衍生生长因子受体A（PDGFRA）基因扩增的患者源性脑肿瘤模型。瑞戈非尼单药可显著抑制神经系统和结缔组织肿瘤来源的所有异种移植物中的肿瘤生长。当瑞戈非尼与辐射和伊立替康联合使用时，观察到分别对PDGFRA扩增的IGRG 93胶质瘤和IGRM 57髓母细胞瘤的增强作用，导致100%的肿瘤消退。抗肿瘤活性与减少肿瘤血管形成、抑制PDGFR信号传导和诱导凋亡性细胞死亡相关。我们的工作表明，瑞戈非尼通过抑制血管生成和诱导细胞凋亡，在广泛的临床前儿科模型中表现出显著的抗肿瘤活性。此外，在PDGFR扩增的肿瘤中观察到DNA损伤剂的放射和化学增敏作用。
The multikinase inhibitor regorafenib (BAY 73–4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.