调节肿瘤通透性增强乳腺癌放疗疗效的研究

Recurrence and metastasis are the main causes of death in breast cancer patients. Radiation therapy plays an important role in the treatment of local recurrence and metastatic breast cancer. Hypoxia is an important factor of resistance to radiotherapy in advanced breast cancer. However, there is a lack of clinically effective methods to reduce hypoxia. New effective strategies to reduce hypoxia and to enhance radiotherapy efficiency are badly needed in radiation therapy for breast cancer. Based on the studies of breast cancer, radiotherapy and tumor-penetrating peptides, this project proposes a scientific hypothesis of using tumor-penetrating peptides to specifically regulate the penetration of tumor tissue and improve the efficacy of radiotherapy. This project will study the effects of tumor-penetrating peptides on breast cancer radiotherapy efficacy, the effect of tumor-penetrating peptides on tumor tissue hypoxia, and the mechanism of tumor-penetrating peptides to improve hypoxia and improve radiotherapy efficacy. This project provides new ideas for radiation therapy for the metastasis and recurrence of breast cancer, and also provides a scientific basis for the model development of enhancing the radiation therapy with tumor-specifically modulating tissue penetration, which has a potential in an independent intellectual property in China and transition to clinical transition.

复发转移是导致乳腺癌患者死亡的主要原因；放射治疗是复发和转移性乳腺癌综合治疗的重要手段之一。乏氧是晚期乳腺癌放疗抵抗的重要原因，但是目前临床中缺乏肿瘤特异性减轻乏氧的有效方法，乳腺癌放射治疗中亟需减轻乏氧提高放疗疗效安全有效的新策略。本课题在申请人前期乳腺癌、放疗以及肿瘤通透肽研究基础上，首次从调节肿瘤通透性出发，提出采用肿瘤通透肽特异地调节肿瘤组织通透性提高放疗疗效的科学假说，并从肿瘤通透肽对乳腺癌放疗疗效的影响、肿瘤通透肽对肿瘤组织乏氧的影响和肿瘤通透肽改善乏氧提高放疗疗效的分子机制三个方面进行研究。本项目为提高复发和转移乳腺癌的放射治疗疗效提供了新思路，也为我国潜在自主知识产权的调节肿瘤通透性增强乳腺癌放疗疗效模式的开发及向临床过渡提供了科学依据。

乏氧是晚期乳腺癌放疗抵抗的重要原因，但是目前临床中缺乏肿瘤特异性减轻乏氧的有效方法，乳腺癌放射治疗中亟需减轻乏氧提高放疗疗效安全有效的新策略。申请人在本项目中发现肿瘤通透肽iRGD和LyP-1联合放疗可以显著抑制肿瘤细胞MCTS的生长和克隆形成能力；动物实验发现肿瘤通透肽联合放疗可以显著地抑制肿瘤的生长和转移；肿瘤通透肽处理后MCTS 和肿瘤组织pimo+细胞比例均下降；肿瘤通透肽联合放疗后MCTS和肿瘤组织的凋亡细胞比例均增加；NRP-1封闭后阻断了肿瘤通透肽对乏氧的影响及对肿瘤细胞放疗增敏作用。本项目为提高复发和转移乳腺癌的放射治疗疗效提供了新思路，也为我国潜在自主知识产权的调节肿瘤通透性增强乳腺癌放疗疗效模式的开发及向临床过渡提供了科学依据。