STM-2457

总的来说，这项研究强调了靶向METTL3可作为改善非小细胞肺癌这种冷肿瘤的免疫治疗效果的有前途的新策略。 肺癌是全球癌症相关死亡的主要原因，每年约有180万人死于肺癌。非小细胞肺癌（NSCLC）是最常见的亚型，约占所有肺癌的85%，其中肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）是NSCLC的两个主要亚型。 虽然PD-1/PD-L1免疫检查点阻断疗法在局部或转移性晚期NSCLC患者中显示出前所未有的疗效，但只有约20%的患者对这些免疫疗法有反应并受益。NSCLC患者对抗PD-1/PD-L1免疫疗法的潜在耐药机制尚不清楚。新的研究证据表明，肿瘤微环境（TME）在调控肿瘤进展和对免疫治疗的反应中发挥关键作用。 根据肿瘤中浸润淋巴细胞（TIL）的数量、PD-L1的表达水平，可以将肿瘤分为两种类型——非炎症性肿瘤（也叫做冷肿瘤）和炎症性肿瘤（也叫做热肿瘤）。冷肿瘤对免疫疗法具有耐药性，而热肿瘤对免疫疗法敏感。将冷肿瘤重编程为热肿瘤，可以显著改善对免疫疗法的反应，从而可能使更多癌症患者受益。 2023年9月25日，武汉大学中南医院张金方教授、哈佛大学医学院魏文毅教授及Gordon Freeman教授等在 Cell 子刊 Cell Chemical Biology 上发表了题为：Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy 的研究论文。 该研究发现，靶向抑制METTL3，能够将冷肿瘤微环境重编程为热肿瘤，让非小细胞肺癌对抗PD-1免疫疗法重新变得敏感。而临床上表现出低METTL3表达的非小细胞肺癌患者接受抗PD-1免疫疗法的预后也更好。 这些结果提示我们，靶向METTL3可作为改善非小细胞肺癌这种冷肿瘤的免疫治疗效果的有前途的新策略。 冷肿瘤以TIL数量少、PD-L1低表达、MHC-I低/缺陷、低肿瘤突变负担和大量免疫抑制细胞（例如骨髓源性抑制细胞和调节性T细胞）为特征，其对免疫疗法具有耐药性。而热肿瘤通常表现为TIL数量多、PD-L1高表达、MHC-I高/完整、高肿瘤突变负担和低免疫抑制细胞浸润，其对免疫疗法敏感。将冷肿瘤重编程为热肿瘤，可以显著改善对免疫疗法的反应，从而可能使更多癌症患者受益。 METTL3/ METTL14介导的m6A修饰，在转录后水平调控基因表达中发挥着至关重要的作用，并影响包括肿瘤发生在内的各种生理病理过程。 METTL3在多种癌症类型中起促肿瘤作用，但也有报道指出METTL3具有抑制肿瘤功能，这提示了METTL3在肿瘤发生中的作用仍有待进一步阐明。 之前有研究显示，在体外培养细胞和免疫缺陷小鼠的异种移植肿瘤模型中，METTL3是促进肺癌发展的致癌基因。近期一项研究利用生物信息学方法对NSCLC中m6A调控因子与肿瘤微环境的相关性进行了分析，但并没有实验证据。METTL3是否以及如何调控肺癌的肿瘤微环境和对免疫治疗反应，仍然是未知的。 在这项最新研究中，研究团队利用肺癌皮下移植小鼠模型、肺癌原位小鼠模型和基因工程小鼠模型来表征METTL3对肺癌肿瘤微环境的调控和对免疫疗法的反应。 研究团队发现，在非小细胞肺癌中，METTL3通过提高促肿瘤趋化因子来招募免疫抑制细胞，并以m6A依赖的方式降低PD-L1表达，从而形成冷肿瘤的肿瘤微环境。而抑制METTL3，能够将冷肿瘤免疫微环境重编程为热肿瘤状态，从而使NSCLC对PD-1免疫疗法重新变得敏感。 具体来说，METTL3提高了促癌趋化因子（包括CXCL1、CXCL5和CCL20）的表达，并以m6A依赖的方式破坏PD-L1的mRNA，从而形成一个冷肿瘤微环境。而使用STM2457（METTL3的特异性小分子抑制剂）抑制METTL3蛋白，或使用shRNA降低METTL3表达水平，均能够将冷肿瘤免疫微环境重编程为热肿瘤状态，使抗PD-1免疫治疗在多种非小细胞肺癌小鼠模型中更有效。 此外，该研究还发现，临床上表现出低METTL3表达的NSCLC患者接受抗PD-1治疗的预后更好。 总的来说，这项研究强调了靶向METTL3可作为改善非小细胞肺癌这种冷肿瘤的免疫治疗效果的有前途的新策略。 武汉大学中南医院张金方教授、哈佛大学医学院魏文毅教授及Gordon Freeman教授为论文共同通讯作者，张金方教授课题组博士后俞海生，哈佛大学 Liu Jing、Bai Xia，解放军总医院第五医学中心马志强为论文第一作者。

Researchers report innovative techniques to treat challenging cancers and manage the side-effects of therapy XI'AN, China, Aug. 9, 2023 /PRNewswire/ -- Although cancer treatment has advanced significantly over the last decade, some fairly common cancers remain extremely difficult to treat. Besides, some chemotherapeutics or anti-cancer drugs can have serious, irreversible side-effects. The latest issue of the JPA features three articles that highlight novel treatment strategies based on cutting-edge research on cancer and chemotherapeutic drug-induced adverse events. Continue Reading Highlights of the Journal of Pharmaceutical Analysis June 2023 issue The first study reports a new approach to prevent hearing loss induced by the widely used chemotherapeutic drug "cisplatin". The article was available online in April 2023 and published in Volume 13, Issue 6 in June 2023. The researchers focused on an inhibitor of protein arginine methyltransferase 5 (PRMT5), a histone-modifying enzyme and epigenetic regulator. In vitro and in vivo experiments revealed that inhibition of PRMT5 alleviated cisplatin-induced mitochondrial dysfunction and apoptosis, and thus ameliorated hearing loss by protecting cochlear hair cells and spiral ganglion neurons. A better understanding of the role of PRMT5 in hearing loss could help scientists develop effective hearing protection drugs and prevent this unwanted side-effect. In this regard, corresponding author Yingzi He states that "Our findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies for hearing loss." In the second study, scientists addressed the problem of inconsistent kinetics of multiple drugs given in a combination therapy. They developed a super-assembled nano-pill that can encapsulate and deliver two different drugs to liver cancer cells. They engineered a supramolecular assembly combining an exportin 1 (XPO1)-inhibiting peptide and a small-molecule inhibitor of ataxia telangiectasia mutated-Rad3-related (ATR). These compounds act synergistically in liver tumors by promoting DNA damage, preventing DNA repair, and arresting the cell cycle. The nano-pills were highly biocompatible with a remarkable therapeutic effect. "This work not only provides a co-delivery strategy for intensive liver cancer treatment with potential for clinical translation, but also extends the scope of drugs for developing advanced combination therapies," highlights the corresponding author Suxia Han. Finally, the third article by Han Xiao et al. presents a comprehensive analysis of the compound STM2457, the novel small-molecule inhibitor of methyltransferase-like 3 (METTL3), which has been reported to promote the disease progression in non-small-cell lung cancer (NSCLC). The authors used a combination of experimental and bioinformatic data to show that STM2457 could significantly inhibit pulmonary colonization and halt NSCLC progression. "The idea of targeting METTL3 is like a "black swan", and its silhouette across the sky was first captured by leukemia and pharmaceutical experts, who synthesized STM2457, the first bioavailable small-molecule inhibitor of METTL3. The cheer of the "black swan" discovery inspired our follow-up work. In the future, targeting the components of translation machinery will become a new therapeutic strategy for NSCLC," states the corresponding author Han Xiao. These studies will pave the way to safer and more effective treatment options for difficult cancers and help improve the quality of life of cancer patients. Reference Authors: Zhiwei Zheng1, Benyu Nan2, Chang Liu3, Dongmei Tang1, Wen Li1, Liping Zhao1, Guohui Nie4, and Yingzi He1 Title of original paper: Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway Journal: Journal of Pharmaceutical Analysis DOI: Contact: Mengjie Wang +86-(0)29-82657423 [email protected].com SOURCE Journal of Pharmaceutical Analysis