PO.CL06.03 · 临床研究
一种靶向IGF-1R的新型"载荷型"多肽LX-101在尤因肉瘤中的体内临床前疗效
In vivo preclinical efficacy of a novel “payload-bearing” peptide LX-101 targeting IGF-1R in Ewing sarcoma
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摘要 Abstract
中文摘要
尤因肉瘤(ES)是一种发生于儿童和青少年的极具侵袭性和高度转移性的骨癌,是儿童患者中第二常见的骨肿瘤。局限性和区域性肿瘤的生存率约为80%,而转移性病例可降至约40%。ES的标准治疗通常包括放疗、手术以及基于VDC/IE方案的化疗。针对在肿瘤发生中具有公认作用的关键通路(如IGF-1、PI3K和mTOR)的替代治疗方法,也已作为单药或联合用药在多种癌症类型中显示出显著的临床活性。因此,确认并生成ES抗癌活性的临床前证据势在必行。在此,我们检测了LX-101的体外和体内疗效。LX-101是一种靶向IGF-1R的新一代疗法,它将一种专有的IGF-1变体与细胞毒性MTX载荷偶联,作为单药或与alpelisib(PI3K抑制剂)和temsirolimus(mTOR抑制剂)联用,在多种ES模型中进行测试。我们检测了LX-101对A-673、ES-8和TC-71细胞系增殖和活力的体外活性。在确认抗增殖活性后,我们评估了所有三种ES细胞系对LX-101与alpelisib和temsirolimus联用的敏感性,估计其对ES培养物活力的协同效应。为进一步证实对ES的细胞毒性效应是由靶向作用介导的,我们通过western blot检测了IGF-1下游效应因子的表达和激活变化,与未暴露细胞相比,所有三种细胞系在LX-101暴露后这些效应因子明显减少,证实LX-101抑制IGF-1R的激活,并提示IGF-1通路受到抑制。最后,我们使用三种不同的PDX尤因肉瘤模型测试了体内活性,分别在有和无alpelisib或temsirolimus的情况下评估协同的临床前疗效。使用定制组织微阵列(TMA)分析评估药效学效应,采用对40种与IGF/PI3K/mTOR信号通路相关的蛋白进行序贯多重免疫荧光。我们的结果表明,LX-101在临床前环境中作为ES的抗癌药物表现出强效的单药活性,而在与抑制PI3K或mTOR的药物联用时活性更强。总体而言,所证明的临床前疗效为推进LX-101进入ES临床试验提供了充分的理论依据。
查看英文原文 English abstract
Ewing sarcoma (ES) is an extremely aggressive and highly metastatic bone cancer in children and young adults, ranked as the second most frequent bone tumor in pediatric patients. With a survival of ~80% for localized and regional tumors, which can drop down to ~40% for metastatic cases, standard treatment for ES usually includes radiotherapy, surgery, and chemotherapy based on the VDC/IE regimen. Alternative therapeutic approaches targeting critical pathways with recognized roles in tumorigenesis, such as IGF-1, PI3K, and mTOR, have also demonstrated remarkable clinical activity as single agents or in combinations for several cancer types. For this reason, it is imperative to confirm and generate preclinical evidence of anticancer activity in ES. Here, we tested the in vitro and in vivo efficacy of LX-101, a next-generation therapy targeting IGF-1R, which couples a proprietary IGF-1 variant to a cytotoxic MTX payload, as a single agent or in combination with alpelisib (a PI3K inhibitor) and temsirolimus (an mTOR inhibitor) in various ES models. We tested the in vitro activity of LX-101 on the proliferation and viability of A-673, ES-8, and TC-71 cell lines. Once anti-proliferative activity was confirmed, we evaluated the sensitivity of all three ES cell lines to the combination of LX-101 with alpelisib and temsirolimus, estimating synergistic effects on the viability of the ES cultures. To consolidate that the cytotoxic effect on ES is mediated by on-target impact, we examined the changes in the expression and activation of IGF-1 downstream effectors by western blot, which were clearly reduced after LX-101 exposure in all three cell lines when compared with non-exposed cells, confirming that LX-101 inhibits the activation of IGF-1R, and indicating the suppression of the IGF-1 pathway. Finally, we tested the in vivo activity using three different PDX Ewing sarcoma models, with and without alpelisib or temsirolimus to assess synergistic preclinical efficacy. The pharmacodynamic effects were evaluated using a custom tissue microarray (TMA) analysis, using sequential multiplex immunofluorescence of 40 proteins related to the IGF/PI3K/mTOR signaling pathway.Our results indicate that LX-101 exhibits potent single-agent activity in the preclinical setting as an anti-cancer agent for ES, and even stronger activity when combined with agents that inhibit PI3K or mTOR. Collectively, the preclinical efficacy demonstrated provides a strong rationale for advancing LX-101 into clinical trials for ES.
利益披露 Disclosure
R. Cardenas-Zuniga, None..
M. Thurm, None..
D. Truong, None.