EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma.

横纹肌肉瘤（Rhabdomyosarcoma, RMS）是儿童最常见的软组织肉瘤，确诊时常伴随远处转移。遗憾的是，目前尚无有效的治疗手段可提升转移性横纹肌肉瘤患儿的长期生存率。本研究探讨了靶向受体酪氨酸激酶EphB4对腺泡状横纹肌肉瘤（alveolar RMS, aRMS）及胚胎型横纹肌肉瘤（embryonal RMS, eRMS）的治疗效果，分别通过抑制性抗体VasG3直接靶向EphB4，或是阻断EphB4与其同源配体EphrinB2结合的正向与反向信号通路实现间接靶向。临床数据显示，eRMS组织中EphB4的表达与更长的生存期呈正相关。实验层面，在aRMS与eRMS的原位异种移植及同种异体移植模型中，使用VasG3抑制EphB4均未能改变肿瘤进展进程；采用融合小鼠血清白蛋白的可溶性EphB4蛋白阻断EphB4正向信号通路时，对eRMS模型的肿瘤进展无显著影响，但可适度延缓小鼠aRMS模型的肿瘤生长。综上，本研究表明，通过上述制剂抑制EphB4信号通路无法作为横纹肌肉瘤的可行单一疗法。