AZD-7762

*仅供医学专业人士阅读参考近年来，免疫治疗，特别是免疫检查点阻断（ICB）疗法，在对抗癌症的战斗中取得了重大进展。然而，部分患者响应较差，因此科学家们一直在寻找方法来提高这种疗法的效果，使更多的患者能够从中受益。四川大学华西医院的郭安源与华中科技大学的甘璐等人联手完成的最新研究，为这个挑战提供了解决方案。论文于近日发表在《自然·免疫学》杂志上。他们通过分析与ICB治疗反应相关的基因组数据，开发了一种名为“CM-Drug”的计算方法，用于预测哪些药物能够与ICB疗法结合使用，以增强其抗癌效果。在多种癌症模型中的验证显示，通过CM-Drug方法预测的药物能够显著增强ICB疗法的效果。其中，CM-Drug预测得到的药物Taltirelin表现出很强的协同效应，通过激活促进T细胞的增殖和活化、改善免疫微环境，来增强ICB治疗黑色素瘤小鼠的疗效。论文首页截图在这项研究中，研究团队首先利用基因集富集分析（GSEA）等技术，对10个数据集的397个癌症患者样本进行分析，试图找出与ICB反应相关的免疫通路。他们识别出4个在治疗响应者中富集的“核心”免疫路径，涉及T细胞受体信号、自然杀伤细胞毒性、抗原处理和呈递等，并据此定义4组核心基因集（C1-C4）；以及2个在治疗响应者中富集的“次要”路径，涉及B细胞受体信号、抗菌作用，并据此定义2组次要基因集（M1和M2）。小鼠肿瘤模型验证表明，这6组基因集在对治疗有反应的小鼠中表达上调。研究团队推测，在联合治疗中，能够上调这6组基因集表达水平的药物，可以提高ICB治疗的抗肿瘤效果。确实如此。研究团队利用联合治疗相关的数据集进行分析，结果显示，在化合物BY001+PD-1抑制剂（GSE132004），或者塞来昔布+PD-1抑制剂（GSE160785），或者低剂量瑞戈非尼+PD-1抑制剂（GSE148947）等特定药物的组合下，这6组基因集表达水平显著上调，与观察到的药效协同作用一致。核心基因集和次要基因集的表达与联合治疗疗效的关系也就意味着，要想为ICB治疗找到一个好的协助者，我们只要筛选找出能够上调这6组基因集表达水平的化合物或药物就行。基于这个原理，研究团队开发了名为“CM-Drug”的计算方法，以预测哪些药物能够与ICB疗法结合使用。CM-Drug利用LINCS L1000数据库中不同肿瘤细胞系的基因表达数据，评估不同化合物或药物对这6组免疫相关基因集的影响，选出候选化合物，并对每个候选化合物进行打分（CM-Score）和排序。原理他们在黑色素瘤模型中验证CM-Drug的性能。通过使用LINCS L1000数据库中的人黑色素瘤细胞系的数据以及计算CM-Score，CM-Drug预测得到3种未被发现与免疫治疗具有协同效应的药物，分别为米格列醇、MG-132和Taltirelin。进一步的黑色素瘤小鼠模型实验结果显示，特别是Taltirelin与PD-1抑制剂的组合，显著增强了抗肿瘤效果，且没有引起显著的毒副作用， 在Taltirelin与PD-1抑制剂联合治疗的组中观察到最长的小鼠生存时间，中位总生存期为43天（PD-1抑制剂单独治疗组为30.5天）。CM-Drug预测得到的三种药物与PD-1抑制剂联合治疗黑色素瘤小鼠的效果进一步的研究结果表明，Taltirelin作为促甲状腺激素释放激素（TRH）类似物，与PD-1抑制剂联合使用时不会导致甲状腺功能紊乱，并通过双重机制发挥协同作用：一方面通过作用于T细胞上的相应受体（TRH-R2）促进其增殖和活化，直接提高T细胞对肿瘤的杀伤效应；另一方面，Taltirelin通过下丘脑-垂体-甲状腺轴调节激素水平，增加树突状细胞对肿瘤细胞的吞噬能力以及抗原呈递能力，间接激活更多的T细胞，改善免疫微环境。Taltirelin增强PD-1抑制剂效果的机制最后，研究团队在肺癌模型中验证CM-Drug的性能。CM-Drug共预测得到536种候选化合物，在CM-Score排名前20的候选药物中，有10种已被报告在与肺癌免疫疗法联用具有明确的抗肿瘤效果。研究团队又挑选了另外6种进行小鼠实验验证，结果显示，除了霉酚酸（MPA），预测得到的5种候选化合物GSK429286A、CGP60474、喜树碱、渥曼青霉素、AZD-7762都可以增强PD-1抑制剂治疗肺癌小鼠的效果。研究团队表示，CM-Drug不仅可以帮助我们从茫茫化合物中筛查候选者，也可以用于评估ICB与其它化合物的联合疗效，比如某些天然植物提取物。这将大大加快ICB联合治疗的药物筛选，并将极大地促进ICB治疗的临床研究。这项研究开辟了一种新的途径，通过基因组学预测可以增强ICB疗法效果的药物，克服了基于传统免疫治疗靶点进行预测或筛选的局限性，为癌症治疗提供了新的希望。参考文献：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41590-024-01789-x本文作者｜张艾迪

A drug currently in clinical trials as a cancer therapy can also stimulate pancreatic beta cells to secrete insulin, revealing a previously unknown mechanism for insulin regulation in type 2 diabetes, according to a new study. The preclinical discovery provides a new chemical tool for probing the biology of diabetes, and could point the way toward better treatments for the disease. A drug currently in clinical trials as a cancer therapy can also stimulate pancreatic beta cells to secrete insulin, revealing a previously unknown mechanism for insulin regulation in type 2 diabetes, according to a new study by Weill Cornell Medicine investigators. The preclinical discovery, reported Nov. 9 in Nature Chemical Biology, provides a new chemical tool for probing the biology of diabetes, and could point the way toward better treatments for the disease. "We have known about insulin for a century, but when it comes to the major mechanisms controlling insulin secretion, there are still a lot of things which are unknown," said senior author Dr. Shuibing Chen, director of the Center for Genomic Health and the Kilts Family Professor of Surgery at Weill Cornell Medicine. To search for new insulin-regulating mechanisms, Dr. Chen and her colleagues, including first author Dr. Angie Chi Nok Chong, a postdoctoral associate in Dr. Chen's lab, began by testing a library of drugs on cultures of mouse pancreatic beta cells, looking for compounds that stimulated insulin secretion in response to glucose. "Instead of running a large-scale drug screening, we decided to do a focused library," said Dr. Chen who is also a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. "So, we had candidates that we knew might be involved in certain important biological processes." The screen identified three compounds that promoted insulin secretion, two of which targeted known insulin-regulating mechanisms in pancreatic beta cells. A third, however, targeted a protein called CHEK2, which is often mutated in cancer but hadn't previously been associated with glucose metabolism. With collaborators at two other institutions, the researchers confirmed that the compound increases glucose-mediated insulin secretion in multiple tests on human and non-human pancreatic cells grown in the laboratory, and various mouse models of type 2 diabetes. "That makes the data very exciting, because it's really consistent from mouse to human islets in vitro, as well as both mouse and nonhuman primate in vivo," said Dr. Chen. Probing the mechanism more closely, the team uncovered a previously unknown insulin secretion-regulating molecular pathway that operates in multiple mammalian species. Dr. Chen says the compound they identified in their initial screen, called AZD7762, promises to be a useful tool for exploring other aspects of insulin regulation. "We not only identified CHEK2 as a potential drug target; we can also use AZD7762 as a chemical probe to find new mechanisms for insulin secretion, and find new targets in the future," she said. While AZD7762 is currently in clinical trials as a cancer therapy, it's unlikely to be directly adapted to a new diabetes treatment. "The safety requirement for cancer therapy and diabetes therapy is completely different," Dr. Chen said, adding that the side effects of the cancer drug would likely make it unsuitable for long-term use in a chronic condition such as type 2 diabetes. Compounds that affect CHEK2 only in pancreatic beta cells, though, could prove very effective. "If we can target delivery of the drugs to beta cells without affecting other cells, that could be an interesting approach to probe," said Dr. Chen. The project has also laid the groundwork for future drug development. "We built up the foundation for the chemical screening and testing in animal and cell models," Dr. Chen said. "In the future if we find anything interesting, it can be immediately tested in this pipeline."