Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases.
Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases.
复制标题
DOI：
10.18632/oncotarget.10292
复制
发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Lanzi C
中科院分区：
文献类型：
--
作者：
Cassinelli G;Favini E;Dal Bo L;Tortoreto M;De Maglie M;Dagrada G;Pilotti S;Zunino F;Zaffaroni N;Lanzi C
硫酸乙酰肝素(HS)模拟/肝素酶抑制剂roneparstat(SST0001)在临床前肉瘤模型中显示出抗肿瘤活性。我们推测，这种100%N-乙酰化和乙二醇化的肝素可以干扰几种在肉瘤中共表达并被肝素结合生长因子激活的受体酪氨酸激酶(RTK)的功能。使用磷酸化蛋白质组学方法，我们研究了药物对代表不同肉瘤亚型的人类细胞株RTK激活的影响。该药抑制成纤维细胞生长因子、胰岛素样生长因子、ERBB和血小板衍生生长因子受体的作用得到了生化和功能验证。Roneparstat抑制COL1A1/PDGFB融合癌基因在原代培养的人皮肤纤维肉瘤原代培养和NIH3T3COL1A1/PDGFB转染体中表达的自分泌环，抑制细胞贴壁非依赖性生长和侵袭。此外，roneparstat还可抑制细胞表面PDGFR的活化和PDGFR相关的FAK，可能有助于逆转NIH3T3COL1A1/PDGFB细胞转化的亲侵袭表型。生化和组织学/免疫组织化学体外分析证实，在药物治疗的尤文肉瘤家族肿瘤异种移植瘤中，ERBB4、EGFR、INSR和IGF1R的活性降低，与诱导细胞凋亡和抑制血管生成有关。罗奈帕司坦与伊立替康联合应用显着提高了对A204横纹肌样移植瘤的抗肿瘤效果，导致了较高的完全应答率和治愈率。这些发现表明，roneparstat对与不同肉瘤亚型的病理生物学相关的RTK具有多靶点抑制作用。这些作用可能与肝素酶抑制作用相配合，有助于该药物的抗肿瘤效果。该研究支持乙酰肝素酶/HS轴靶向作为不同肉瘤亚型联合治疗的一种有价值的方法，为临床研究提供了临床前的理论基础。
The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.