动态活细胞成像研究MDSCs在多发性骨髓瘤耐药中的作用及其分子机制

Multiple myeloma (MM) is a hematologic malignancy which remains incurable mostly because of the development of drug resistance. New drugs and the combinative therapy have been used in order to overcome the drug resistance of MM. In our previous study we observed synergistic antimyeloma effect with the combination of γ-secretase inhibitor (GSI) and bortezomib, but the same effect was not found in vivo. Our further investigation indicated that myeloid derived suppressor cells (MDSCs) were responsible for the drug resistance of MM. Although a significant correlation between circulating MDSCs and clinical cancer stage has been observed, their role in drug resistance especially in MM has to be defined yet. In this proposal, we expect to determine the interaction between MDSCs and MM cells based on dynamic imaging of living cells and high content screening.We attempt to verify the molecular mechanisms underlying drug resistance of MM induced by MDSCs. Using high-content screening system, we will screen different drugs or drug combinations based on targeting the interaction between MDSCs and MM cells. The goal of this proposal is to understand the role of MDSCs in the drug resistance of MM and to optimize the treatment strategy of the disease.

多发性骨髓瘤（MM）是不能治愈的血液系统恶性肿瘤，多数病人由于耐药导致疾病难治和复发，新药开发和联合用药是克服MM耐药的主要研究方向。我们在前期工作中发现：联合γ分泌酶抑制剂（GSI）和硼替佐米（MM主要治疗药物）治疗MM，在体内和体外实验中出现矛盾结果，进一步研究提示髓系来源抑制性细胞（MDSCs）参与介导了MM的耐药。MDSCs与多种肿瘤发病相关，但MDSCs与肿瘤耐药、尤其MM耐药的关系尚罕有报道。本项目拟建立MM原位移植瘤荷瘤小鼠模型，利用动态活细胞成像和高内涵筛选的技术平台，采用MDSCs与MM细胞共培养方式，深入探讨MDSCs在MM耐药中的作用与分子机制；针对阻断MDSCs和MM相互作用的一些药物进行筛选和组合，在体外和体内水平验证上述药物/组合的疗效。预期目标的实现将会明确MDSC在MM发生、发展及其耐药的影响，筛选出新型药物/组合，为MM新的治疗策略提供实验室依据。

多发性骨髓瘤（MM）是不能治愈的血液系统恶性肿瘤，多数病人由于耐药导致疾病难治和复发，新药开发和联合用药是克服MM耐药的主要研究方向。髓系来源抑制性细胞（MDSCs）与多种肿瘤发病相关，但MDSCs与肿瘤耐药、尤其MM耐药的关系尚罕有报道。本研究利用动态活细胞成像和高内涵筛选的技术平台，探讨MDSCs在MM耐药中的作用与分子机制。研究发现作为骨髓微环境中的重要成分，MDSCs在MM耐药中起到一定作用，共培养条件下MM细胞对阿霉素的耐药性明显大于MM细胞单独培养，通过对抗骨髓瘤药物组合的检测和筛选发现Carfilzomib+马法兰、Carfilzomib+硼替佐米组合对逆转MDSCs介导的MM耐药有一定治疗作用，上述药物组合可能通过细胞凋亡信号通路的诱导逆转MM耐药。本研究可为MM新的治疗策略的提出提供实验室依据。