LDH预测bevacizumab治疗转移性结直肠癌疗效的机制及新靶点的探索性研究

No validated biomarker currently exists for bevacizumab. Recently LDH shows great potential for predict patients who can benefit from bevacizumab, although the mechanism remains elusive. We suspect that hypoxia and aerobic glycolysis in tumor microenvironment serve as the basis for the predict role of LDH. Our previous work shows that only patients who were with elevated LDH could get benefit from bevacizumab; and the vessels without pericyte coverage is related to LDH levels and the efficacy of bevacizumab; LDH increases lactate production, promotes invasion of endothelial cells while inhibits invasion of pericyte, and facilitates endothelial cell and pericyte secrete TGF-β under hypoxia condition; symbiosis exists in metastatic colorectal cancer and the distribution of MCT-1 is related with vessels without pericyte coverage. We plan to explore the mechanism by which the vessel without pericyte coverage generated, which might be results of lactate induced endothelial cells activation via VEGFR-2 and pericyte inhibition via TGF-β receptor, and both of them are in a HIF1α dependent pathway. What’s more, we plan to examine the impact of MCT-1 knockout on tumor grows and angiogenesis. By all of the above experiments, we aim to study the reason why LDH could predict the efficacy of bevacizumab, and evaluate whether vessel without pericyte coverage is with better predict value, as well as the therapeutic role of MCT-1.

Bevacizumab缺乏可靠的疗效预测指标，最近LDH却显示了潜在价值，机制不明！可能与以缺氧和有氧糖酵解为特征的肿瘤微环境相关。我们发现只有LDH升高的mCRC才有生存获益，且LDH与乏周细胞的血管数量相关，后者与bevacizumab敏感性相关；预试验提示LDH增加乳酸生成，乳酸促进血管内皮细胞迁徙和抑制周细胞迁徙，在缺氧状态下促进两者分泌TGF-β；肿瘤微环境中存在共生现象，共生关键分子MCT1与乏周细胞血管分布一致。本课题拟探讨微环境中LDH/乳酸以依赖HIF-1α方式通过 VEGFR-2促进内皮细胞生长、通过TGF-β受体抑制周细胞迁徙，从而生成大量乏周细胞的血管；敲除肿瘤微环境中的MCT1来阻断乳酸的利用，从而杀伤肿瘤和减少乏周细胞的血管生成；旨在阐明LDH预测bevacizumab疗效的机制，进而提出乏周细胞的血管是更加个体化的疗效预测指标以及MCT1是抗血管生成的新靶点！

Bevacizumab缺乏可靠的疗效预测指标，探索其疗效预测指标筛选优势人群、提高疗效是临床的实际需求。第一，LDH升高、乏周细胞血管（CD31+/α -SMA-）与bevacizumab治疗获益相关。第二，机制探索。LDH升高促进乳酸生成。乳酸摄取关键蛋白MCT1的高表达也与bevacizumab疗效相关。乳酸通过稳定HIF-1α蛋白，诱导MCT1阳性肠癌细胞分泌VEGF并促进内皮细胞管腔形成，进而促进肿瘤血管新生。这类依赖VEGF的新生血管对bevacizumab治疗敏感。这为下一步研究提高bevacizumab疗效的新靶点提供理论基础。第三，bevacizumab的潜在疗效预测指标以及预后指标。首先，左半结肠癌及直肠癌，CA199升高，血清载脂蛋白A-I升高的患者更可能从bevacizumab治疗中获益。其次，发现高LDH、高CA199、高NLR、低载脂蛋白A提示预后较差。再次，可手术患者中，阴性淋巴结数目及比例较高提示预后较好。相对于改良的GPS炎症预后评分（mGPS），系统炎症反应评分（SIS），我们创建的白蛋白-NLR炎症模型是更优的预后指标。此外，III期结肠癌中，骨骼肌缺乏与高系统性炎症反应有关，DFS较短。第四，我们报道了免疫治疗在多瘤种中的近期疗效，并发现拓扑异构酶II抑制剂可以通过cGAS/STING通路，激活DC和T淋巴细胞，提高肿瘤的免疫原性，提高PD-1单抗的疗效。dMMR/ MSI-H是目前实体瘤免疫治疗的预测指标之一。我们的研究提示dMMR/ MSI-H患者患多种原发肿瘤风险增加，且肿瘤免疫微环境更为复杂，TIL及PD-L1表达增多，可能是这类患者免疫治疗有效的机制之一。而在原发灶为MSI-H的结直肠癌，在转移至腹膜及卵巢时可能出现变为MSS。