Jagged1/Notch1信号活化介导的肾癌干细胞样表型促进舒尼替尼耐药的分子机制及克服策略研究

The VEGFR/PDGFR kinase inhibitor sunitinib is a promising strategy for patients with advanced renal cell carcinoma (RCC). However, preclinical and clinical observations indicated that this therapy may have limited efficacy.Although sunitinib typically produces inhibition of primary tumor growth, lasting responses are rare, with only a moderate increase in progress-free survival and little benifit in overall survival. In addition, when sunitinib is administered on an intermittent schedule, tumor regrowth is sometimes seen during drug-free periods or upon discontinuation of treatment. It was reported that receptor tyrosine kines inhibitors could increase cancer stem cells via generating tumor hypoxia, which contributed to the drug resistance. Also, Notch1 signaling pathway is involved in the hypoxia-induced cancer stem cells. Importantly, our previous study demonstrated that aberrent Jagged1/Notch1 pathway activation plays an important role in the tumorigenesis of RCC regaredless of the VHL status. Thus, we hypothesize that sunitinb treatment aggravates hypoxia in tumor microenvironment, which in turn leads to Notch1 activation,cancer stem cell accumulation and finally sunitinib resistance. In this study, we aim to test our hypothesis and establish a model of molecular regulation and therapeutic intervention of sunitinib resistance,and seek to reverse acquired sunitinib resistance through suppressing Jagged1/Notch1 signaling pathway.

受体酪氨酸激酶抑制剂舒尼替尼已经广泛用于晚期肾癌的治疗，但是患者均在治疗后数月出现耐药而致治疗失败。因此，阐明肾癌舒尼替尼耐药的分子机制对逆转治疗抵抗和开发新的治疗方案至关重要。我们前期研究表明Jagged1/Notch1信号通路的活化在肾癌的发生过程中起重要作用，并且Notch1信号活化可以增强肾癌干细胞样表型、降低对舒尼替尼的敏感性。本申请项目以舒尼替尼耐药的裸鼠模型、舒尼替尼新辅助治疗的临床标本和人肾癌细胞系为研究对象，围绕HIF-1α与Jagged1/Notch1信号通路的交互通话所介导的肾癌干细胞样表型而展开，通过针对性抑制Jagged1/Notch1信号通路活性来逆转治疗抵抗，从而建立肾癌舒尼替尼耐药的分子调控和治疗干预模型，为克服舒尼替尼治疗抵抗的药物开发和临床研究奠定基础。

大量研究证实肿瘤微环境对肾癌的进展和转移起到重要作用。基于本项目，我们研究发现瘤内肿瘤相关巨噬细胞呈现M2 极化状态的肾癌患者存在着较差的预后（Ann Surg Oncol. 2014, 21(9):3142-50.通讯作者）。另外，肾癌患者术前一周内外周血中淋巴细胞计数与单核细胞计数比值（lymphocyte-to-monocyte ratio, LMR）的降低与肿瘤的高分期、低分化以及不良的术后总体生存显著相关，进而联合LMR 和血浆白蛋白水平建立全身炎症反应评分，该评分结合肿瘤TNM 分期、Fuhrman 分级 和淋巴微血管浸润情况可以为肾癌患者提供更加精准的术后生存风险评估（Br J Cancer. 2015;113(4):626-33.通讯作者）。我们发现，肾癌细胞可以通过分泌CCL2招募外周循环中单核细胞迁移至肿瘤组织并分化为肿瘤相关巨噬细胞从而促进肿瘤生长。肾癌组织内高表达CCL2 的患者术后5 年和10 年无复发生存率显著低于CCL2低 表达的患者，将CCL2 整合入现有的肾癌预后模型可以显著提高其预测准确性 （Urol Oncol. 2016;34(5):238 e19-26.通讯作者）。进一步研究免疫相关分子，研究发现肾癌中CXCR2 的表达显著高于相应的正常肾组织，而且CXCR2 的表达水平与肿瘤的大小、分级、分期以及患者的预后密切相关（Eur J Cancer. 2015,51:1953-1961.通讯作者）。进一步，我们研究发现血管逆天阳性肾癌患者比血管生成拟态阴性患者术后肿瘤远处转移风险显著升高，提示血管生成拟态形成在肾癌转移发生过程中的重要作 用(J Urol. 2016; 196(2):335-42.通讯作者)。这些研究结果为肾癌的新型分子靶向药物开发奠定基础。