Châtre Rémi, Blochouse Estelle, Eid Rony, Djago Fabiola, Lange Justin, Tarighi Mehrad, Renoux Brigitte, Sobilo Julien, Le Pape Alain, Clarhaut Jonathan, Geffroy Claude, Opalinski Isabelle, Tuo Wei, Papot Sébastien, Poinot Pauline
University of Poitiers, UMR CNRS 7285, Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Equipe Labellisée Ligue Contre le Cancer 4 Rue Michel-Brunet, TSA 51106 86073 Poitiers Cedex 9 France
UAR No. 44 PHENOMIN TAAM-Imagerie In Vivo, CNRS 3B Rue de la Férollerie F-45071 Orléans France.
Chem Sci. 2023 Apr 11;14(18):4697-4703. doi: 10.1039/d2sc06797h. eCollection 2023 May 10.
The discovery of tumour-associated markers is of major interest for the development of selective cancer chemotherapy. Within this framework, we introduced the concept of induced-volatolomics enabling to monitor simultaneously the dysregulation of several tumour-associated enzymes in living mice or biopsies. This approach relies on the use of a cocktail of volatile organic compound (VOC)-based probes that are activated enzymatically for releasing the corresponding VOCs. Exogenous VOCs can then be detected in the breath of mice or in the headspace above solid biopsies as specific tracers of enzyme activities. Our induced-volatolomics modality highlighted that the up-regulation of -acetylglucosaminidase was a hallmark of several solid tumours. Having identified this glycosidase as a potential target for cancer therapy, we designed an enzyme-responsive albumin-binding prodrug of the potent monomethyl auristatin E programmed for the selective release of the drug in the tumour microenvironment. This tumour activated therapy produced a remarkable therapeutic efficacy on orthotopic triple-negative mammary xenografts in mice, leading to the disappearance of tumours in 66% of treated animals. Thus, this study shows the potential of induced-volatolomics for the exploration of biological processes as well as the discovery of novel therapeutic strategies.
肿瘤相关标志物的发现对于选择性癌症化疗的发展至关重要。在此框架内，我们引入了诱导挥发组学的概念，能够同时监测活体小鼠或活检组织中多种肿瘤相关酶的失调情况。这种方法依赖于使用基于挥发性有机化合物（VOC）的探针混合物，这些探针通过酶促激活来释放相应的VOC。然后，可以在小鼠呼出的气体或固体活检组织上方的顶空中检测到外源性VOC，作为酶活性的特异性示踪剂。我们的诱导挥发组学方法突出表明，β-乙酰氨基葡萄糖苷酶的上调是几种实体肿瘤的一个标志。在将这种糖苷酶确定为癌症治疗的潜在靶点后，我们设计了一种酶响应性白蛋白结合前药，即强效单甲基澳瑞他汀E，其可在肿瘤微环境中选择性释放药物。这种肿瘤激活疗法对小鼠原位三阴性乳腺异种移植物产生了显著的治疗效果，导致66%的治疗动物体内肿瘤消失。因此，这项研究显示了诱导挥发组学在探索生物学过程以及发现新型治疗策略方面的潜力。
