PO.ET09.07 · 实验与分子治疗
用HBS-101靶向midkine驱动的致癌信号：一种针对肺癌的新型治疗策略
Targeting midkine-driven oncogenic signaling with HBS-101: A novel therapeutic strategy for lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Midkine（MDK）是一种肝素结合生长因子，在非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）中异常过表达，通过PI3K/Akt、MAPK/ERK和Notch通路驱动肿瘤进展、血管生成、EMT和治疗耐药。尽管低剂量计算机断层扫描（LDCT）肺癌筛查取得了进展，但高假阳性率、累积辐射暴露和欠佳的敏感性仍是主要问题。这些局限性凸显了对新型、非侵入性生物标志物的需求，以增强早期检测并指导靶向疗法的开发。血清和尿液中的循环MDK是一种有前景的生物标志物，而HBS-101是一种同类首创的小分子抑制剂，可选择性阻断MDK-受体相互作用及下游致癌信号，提供一种生物标志物指导的疗法。使用癌症基因组图谱计划（TCGA）和基因型-组织表达（GTEx）数据分析了MDK在肿瘤组织和正常组织中的表达。在体内使用SW1573 NSCLC异种移植模型（腹腔注射HBS-101，5或10 mg/kg，持续56天）以及在体外使用3D SCLC类器官模型（SB-17-54，浓度范围0-200 μM）评估HBS-101的抗肿瘤疗效，以确定IC50值。监测了肿瘤生长、体重、全身毒性和基因表达。RNA分析显示MDK在NSCLC和SCLC中广泛过表达，与匹配的正常组织相比，肺腺癌和鳞状细胞癌中的水平显著升高。HBS-101治疗在NSCLC异种移植中导致了具有统计学意义的剂量依赖性肿瘤生长抑制，与对照组相比肿瘤体积减少55-60%（p<0.01），且无全身毒性。在SCLC类器官中，HBS-101表现出强效的生长抑制，IC50为5.09 μM。正在进行的工作包括合成荧光MDK衍生物和HBS-101类似物，以阐明受体相互作用并实现高通量筛选，以及在EGFR突变的NSCLC细胞系（PC-9、H1975）及其Osimertinib耐药衍生系中分析MDK，旨在明确MDK轴及其在治疗耐药中的作用。总的来说，我们的研究结果验证了MDK既是一种循环生物标志物又是一个可成药靶点，并将HBS-101定位为有前景的精准肺癌治疗候选药物。如果得到验证，MDK抑制可以克服EGFR-TKI耐药，并实现基于MDK的患者分层，指导下一代抑制剂和早期检测策略。
查看英文原文 English abstract
Midkine (MDK), a heparin-binding growth factor, is aberrantly overexpressed in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), where it drives tumor progression, angiogenesis, EMT, and therapy resistance via PI3K/Akt, MAPK/ERK, and Notch pathways. Despite progress with low-dose computed tomography (LDCT) screening for lung cancer, high false-positive rates, cumulative radiation exposure, and suboptimal sensitivity are still major concerns. These limitations underscore the need for novel, noninvasive biomarkers to enhance early detection and guide the development of targeted therapies. Circulating MDK in serum and urine is a promising biomarker, and HBS-101, a first-in-class small-molecule inhibitor, selectively blocks MDK-receptor interactions and downstream oncogenic signaling, offering a biomarker-guided therapy.MDK expression was analyzed across tumor and normal tissues using The Cancer Genome Atlas Program (TCGA) and the Genotype-Tissue Expression (GTEx) data. Anti-tumor efficacy of HBS-101 was evaluated in vivo using an SW1573 NSCLC xenograft model treated intraperitoneally with HBS-101 (5 or 10 mg/kg) for 56 days and in vitro using a 3D SCLC organoid model (SB-17-54) across 0-200 µM to determine IC₅₀ values. Tumor growth, body weight, systemic toxicity, and gene expression were monitored.RNA analyses revealed broad MDK overexpression in both NSCLC and SCLC, with significantly elevated levels in lung adenocarcinoma and squamous cell carcinoma compared to matched normal tissues. HBS-101 treatment led to a statistically significant dose-dependent tumor growth inhibition in NSCLC xenografts, reducing tumor volume by 55-60% compared to control (p<0.01) without systemic toxicity. In SCLC organoids, HBS-101 demonstrated potent growth inhibition with an IC₅₀ of 5.09 µM.Ongoing works include synthesizing fluorescent MDK derivatives and HBS-101 analogues to elucidate receptor interactions and enable high-throughput screening, and profiling MDK in EGFR -mutated NSCLC cell lines (PC-9, H1975) and their Osimertinib-resistant derivatives aim to define the MDK axis and its role in therapeutic resistance. Taken together, our findings validate MDK as both a circulating biomarker and a druggable target, and position HBS-101 as a promising candidate for precision lung cancer therapy. If validated, MDK inhibition could overcome EGFR-TKI resistance and enable MDK-based patient stratification, guiding next-generation inhibitors and early detection strategies.
利益披露 Disclosure
R. Borea, None..
F. Drago, None..
M. Sammour, None..
N. Giovanni, None..
S. Li Zhao, None..
B. R. Peterson, None..
H. B. Nair, None..
C. Rolfo, None..
E. Shankar, None.