基于SHP-2通过PI3K/AKT和Erk调控ZEB1-miR-200反馈环的前神经元型高度恶性胶质瘤个体化治疗策略初探

The high-grade glioma is the most common primary malignant brain tumors in adult, and is poorly responsive to all the current treatment strategies. There leaves urgent needs for developing new individualized treatment strategies for patients with different subtypes of high-grade glioma. Our latest study found that SHP-2 regulated the ZEB1-miR-200 feedback loop through PI3K / AKT and Erk in platelet derived growth factor receptor α (PDFGRα) driven tumoriogenesis and progression of proneural (PN)-subtype of high-grade glioma. Our pre-experimental results suggested that the SHP-2 inhibitors significantly inhibited proliferation of PN-subtype of high-grade glioma cell lines, meanwhile enhancing their epithelium-like properties. In contrast, SHP-2 inhibitors didn’t inhibit proliferation of mesenchymal-subtype of cell lines, and even promoted cell proliferation at low doses. The project intends to explore the effects of SHP-2 inhibitors themselves, together with temozolomide or radiotherapy on proliferation, invasion and epithelial-mesenchymal transition (EMT) of cell lines as well as cancer stem cells of both PN-subtype and mesenchymal-subtype of high-grade glioma. Furthermore, in vivo therapeutic effects of SHP-2 inhibitors themselves, together with temozolomide or radiotherapy on orthotopic transplanted tumor models in nude mice of cell lines as well as cancer stem cells of both PN-subtype and mesenchymal-subtype of high-grade glioma will be investigated. The specific therapeutic effects and molecular mechanism of SHP-2 inhibitors themselves, together with temozolomide or radiotherapy on PN-subtype of high-grade glioma will be explored to provide theoretical basis for individualized precision medicine of PN-subtype of high-grade glioma.

高度恶性胶质瘤是成人最常见的原发恶性脑肿瘤，治疗反应差。亟需为不同分型高度恶性胶质瘤患者研发个体化治疗新策略。我们的最新研究发现SHP-2通过PI3K/AKT和Erk调控ZEB1-miR-200反馈环介导PDFGRα驱动的前神经元(Proneural，PN)型高度恶性胶质瘤发生发展。前期预实验提示SHP-2抑制剂对PN型高度恶性胶质瘤细胞株的增殖抑制率较对照显著增强，并强化PN型细胞株的上皮样特性；而对间充质型细胞株的增殖抑制率较对照显著降低，在低剂量时甚至促进细胞增殖。本项目拟研究SHP-2抑制剂及其与替莫唑胺或放疗联用对PN型和间充质型高度恶性胶质瘤细胞株与肿瘤干细胞增殖、侵袭及EMT的影响，及其裸鼠原位移植瘤模型体内治疗效应的差异，探讨SHP-2抑制剂及其与替莫唑胺或放疗联用对PN型高度恶性胶质瘤潜在的特异性治疗效应及分子机制，为PN型高度恶性胶质瘤的“个体化精准医疗”提供理论依据。

目前高度恶性胶质瘤的常规治疗方案是术后替莫唑胺同步放化疗加替莫唑胺辅助治疗。然而，即使再联合使用生物免疫疗法等诸多治疗方案，高度恶性胶质瘤患者的平均生存期仍然不足两年。因此，亟需依据不同分型高度恶性胶质瘤的发生发展分子机制探寻针对性、个体化新型治疗药物，从而为高度恶性胶质瘤患者的“个体化精准医疗”提供理论依据和治疗策略。本项目经过前期的靶向小分子筛选和后期体内外实验验证，发现了SHP099这一潜在的具有极好转化前景的SHP-2的小分子药物，能有效地靶向神经胶质瘤干细胞，它能特异性诱导前神经元型胶质瘤细胞株的细胞周期阻滞，SHP099特异性抑制PDGFRα‒SHP-2刺激的ERK1/2活性可能是其潜在机理。SHP099口服后血脑屏障通透性高。在裸鼠原位移植瘤小鼠模型，SHP099单独给药或者与TMZ联用均能显著延长荷瘤小鼠的生存期，有望为该亚型的胶质瘤治疗提供新策略。