基于循证医学证据的中药榄香烯治疗肺癌靶标发现及逆转TKI耐药机制探究

Elemene is a novel anti-tumor drug with invention patents created by our team through 20 years, according to the theory “Eliminating mass and resolving the knots, eliminating pathogen and strengthening vital qi” in TCM and “Molecular compatibility” in Integrated Traditional Chinese and Western Medicine, is found and extracted Elemene from Curcuma with the function of “Eliminating mass and resolving the knots, and letting blood and relieving pain”, and as targeted liposome preparations. The evidence-based medicine (EBM) evaluation proved safe and has good antitumor activity to lung cancer, liver cancer, brain cancer and so on. But its action targets and the mechanism of reversing drug resistance are unclear. Elemene as a small molecule drug is very difficult to determine the target protein using the conventional methods. This project intends to combine with clinical research, use such new proteomics technologies of cellular thermal shift assay (CETSA) and thermal proteome profiling (TPP) to explore the action targets of elemene such as protein, mRNA, miRNA and DNA in lung cancer cells with no drug resistance and TKI resistance, to analyze and verify the targets, gene regulatory networks and molecular mechanism of Elemene treatment for lung cancer and reversing TKI resistance by bioinformatics. In addition, the project will also use the technology of mesoporous silica nanoparticles (MSNPs) to achieve organelles target and molecular target, and to confirm further the targets and molecular mechanism of Elemene for the treatment of lung cancer. With this project completed, it will provide the evidence concerning the target proteins identification of Elemene, the clarification of mechanisms reversing TKI resistance, and clinical application by combining with TKI. The relevant research results will offer help for the cancer treatment of combining traditional Chinese and western medicine, and for the internationalization of traditional Chinese medicine.

榄香烯是申请人历经二十多年研发具有发明专利的抗癌新药，依据中医“消癥散结、祛邪扶正”治疗癌症和中西医结合的“分子配伍”理论，从“消癥散结，破血止痛”的中药温郁金发现并提取抗癌成分榄香烯，用脂质体靶向制剂精制而成，循证医学评价证实对肺癌、肝癌、脑癌等安全有效，但目前靶标及逆转耐药机制尚不明确。榄香烯是小分子药物，按常规方法难以确定靶标，本项目结合临床研究，采用细胞热转变、热蛋白组图谱等新技术，探寻榄香烯在不耐药及TKI耐药肺癌细胞的蛋白、mRNA、miRNA和DNA等靶标，利用生物信息学等方法分析验证榄香烯治疗肺癌和逆转TKI耐药的靶标、基因调控网络与分子机理。利用介孔二氧化硅纳米粒技术实现细胞器及分子靶向，进一步证实榄香烯治疗肺癌及逆转耐药的靶标与分子机理。本项目完成将为榄香烯靶标的鉴定、逆转TKI耐药机制的阐明以及联合TKI临床推广应用提供证据，为中西医结合治疗癌症及中药国际化提供帮助。

EGFR-TKIs耐药是EGFR突变敏感型肺癌治疗失败的重要原因。中医认为气滞血瘀是肺癌复发耐药的主要病机。榄香烯是申请人历经二十多年研究，在中医“消癥散结、扶正祛邪”治疗癌症思路及中西医结合的“分子配伍”理论指导下，从“消癥散结、破血止痛”中药温郁金中发现的高效低毒抗癌活性成分。临床前研究显示榄香烯能够逆转肺癌细胞对吉非替尼的耐药，但具体分子机制不明。本研究首先证实β-榄香烯可通过m6A甲基转移酶METTL3和lncRNA H19介导的自噬逆转NSCLC细胞对吉非替尼的耐药。其次，利用介孔二氧化硅纳米技术，合成一种新型榄香烯纳米药物，促进了榄香烯的靶向递送，进一步证实了榄香烯逆转肺癌细胞对吉非替尼耐药的机理。进一步，临床研究显示榄香烯联合EGFR-TKIs治疗EGFR突变阳性的晚期非小细胞肺癌显著延长了患者的无疾病进展时间，同时可获得较高的疾病控制率，并显著改善了患者的生活质量。该研究对于克服EGFR-TKIs耐药和开展靶向性的个体化治疗都具有十分重要的意义。