Gerard Louise, Duvivier Laurent, Gillet Jean-Pierre
Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Namur, Belgium.
Fac Rev. 2021 Jan 26;10:6. doi: 10.12703/r/10-6. eCollection 2021.
Cancer develops resistance to treatments through many mechanisms. Single-cell analyses reveal the intratumor heterogeneity and dynamic relationships between cancer cell subpopulations. These analyses also highlight that various mechanisms of resistance may coexist in a given tumor. Studies have unraveled how the microenvironment affects tumor response to treatments and how cancer cells may adapt to these treatments. Though challenging, individualized treatment based on the molecular characterization of the tumor should become the new standard of care. In the meantime, the success rate of clinical trials in oncology remains dramatically low. There is a need to do better and improve the predictability of preclinical models. This requires innovative changes in models and the culture system currently being used. An innovative ligand design is also urgently needed. The limited arsenal of medicinal chemistry reactions and the biases of scaffold selection favor structurally similar compounds with linear shapes at the expense of disc and spherical shapes, which leave a large chemical shape space untouched. In this regard, venoms have received increasing interest as a wellspring for drug candidates. Overall, the characterization of tumor heterogeneity has contributed to advancing our understanding of the mechanisms that underlie cancer resistance to treatments. Targeting these mechanisms will require setting key milestones to significantly improve the translatability of preclinical studies to the clinic with the hope of increasing the success rate of clinical trials.
癌症通过多种机制对治疗产生耐药性。单细胞分析揭示了肿瘤内的异质性以及癌细胞亚群之间的动态关系。这些分析还突出表明，在给定肿瘤中，多种耐药机制可能同时存在。研究已经阐明了微环境如何影响肿瘤对治疗的反应以及癌细胞如何适应这些治疗。尽管具有挑战性，但基于肿瘤分子特征的个体化治疗应成为新的护理标准。与此同时，肿瘤学临床试验的成功率仍然极低。有必要做得更好并提高临床前模型的可预测性。这需要对当前使用的模型和培养系统进行创新性改变。还迫切需要创新的配体设计。药物化学反应的有限手段以及支架选择的偏差有利于具有线性形状的结构相似化合物，而牺牲了圆盘状和球状形状，从而留下了大量未被触及的化学形状空间。在这方面，毒液作为候选药物的来源受到了越来越多的关注。总体而言，肿瘤异质性的表征有助于推进我们对癌症耐药治疗潜在机制的理解。针对这些机制将需要设定关键的里程碑，以显著提高临床前研究向临床的转化能力，希望提高临床试验的成功率。
