The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma.
The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma.
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DOI：
10.1186/s13045-016-0377-8
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发表时间：
2017-01-05
影响因子：
28.5
通讯作者：
Festuccia C
中科院分区：
文献类型：
--
作者：
Gravina GL;Mancini A;Marampon F;Colapietro A;Delle Monache S;Sferra R;Vitale F;Richardson PJ;Patient L;Burbidge S;Festuccia C
使用抗血管内皮生长因子（VEGF）抗体贝伐珠单抗治疗后胶质母细胞瘤复发的特点是高度浸润和恶性行为，导致手术切除和化疗无效。已经证明，抗 VEGF/VEGFR 疗法可以控制侵袭性表型，并且通过增加 CXCR4 的活性来发生复发。因此，我们假设贝伐珠单抗或舒尼替尼与新型 CXCR4 拮抗剂 PRX177561 组合将具有优异的抗肿瘤活性。在 U87MG、U251 和 T98G 细胞的皮下异种移植物以及注射到 CD1-nu/nu 小鼠中的荧光素酶标记 U87MG 细胞的颅内异种移植物中，测试了贝伐单抗、舒尼替尼和 PRX177561 单独或联合使用的效果。动物被随机分配接受媒介物、贝伐单抗（4 mg/kg 静脉注射，每 4 天）、舒尼替尼（40 mg/kg 口服，每日一次）或 PRX177561（50 mg/kg 口服，每日一次）。体内实验表明，贝伐珠单抗和舒尼替尼可增加 CXCR4、SDF-1α 和 TGFβ1 的体内表达。此外，我们证明新型脑穿透性 CXCR4 拮抗剂 PRX177561 与贝伐单抗或舒尼替尼共同给药可抑制肿瘤生长并减少炎症。 PRX177561与贝伐单抗的组合可协同减少肿瘤生长，增加无病生存期（DSF）和总生存期（OS），而PRX177561与舒尼替尼的组合则显示出轻微的相加效应。 CXC4 拮抗剂 PRX177561 可能是抗血管生成疗法的有效补充疗法，特别是与 VEGF/VEGFR 抑制剂联合使用时。因此，该化合物值得考虑用于未来的临床评估。
Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity. The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd). The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect. The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
--
作者：
Kessler T;Sahm F;Blaes J;Osswald M;Rübmann P;Milford D;Urban S;Jestaedt L;Heiland S;Bendszus M;Hertenstein A;Pfenning PN;Ruiz de Almodóvar C;Wick A;Winkler F;von Deimling A;Platten M;Wick W;Weiler M
通讯作者：
Weiler M
影响因子：
3.8
作者：
Gravina GL;Mancini A;Sanita P;Vitale F;Marampon F;Ventura L;Landesman Y;McCauley D;Kauffman M;Shacham S;Festuccia C
通讯作者：
Festuccia C
影响因子：
--
作者：
Cortes-Santiago N;Hossain MB;Gabrusiewicz K;Fan X;Gumin J;Marini FC;Alonso MM;Lang F;Yung WK;Fueyo J;Gomez-Manzano C
通讯作者：
Gomez-Manzano C
影响因子：
2.8
作者：
Gravina, Giovanni Luca;Marampon, Francesco;Festuccia, Claudio
通讯作者：
Festuccia, Claudio