Department of Neuroscience, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
Research Center for Functional Genomics, Biomedicine and Translational Medicine, The "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
Expert Rev Mol Med. 2023 May 8;25:e18. doi: 10.1017/erm.2023.10.
Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile.
A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway.
Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis.
This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.
胶质母细胞瘤（GBM）是最常见的原发性脑癌，中位生存期仅为 15 个月。目前的标准治疗包括手术、放疗（RT）和替莫唑胺化疗，但效果有限。此外，多项研究表明，肿瘤复发和对经典治疗方法的耐药性是常见事件，大多数患者都会发生，最终导致死亡。需要新的方法来更好地了解胶质母细胞瘤中涉及的复杂肿瘤生物学，以便开发个性化的治疗方法。癌症生物学的进步拓宽了我们对 GBM 基因组的理解，并允许根据其分子特征对这些肿瘤进行更好的分类。
目前，在 GBM 的多项临床试验中正在研究的一种新的靶向治疗方法是针对 DNA 损伤修复（DDR）途径中各种缺陷的分子，该途径是一种由内源性和外源性因素激活的机制，这些因素会导致 DNA 改变，并参与化疗和 RT 耐药性的发展。这个复杂的途径受 p53、两个重要的激酶 ATR 和 ATM 以及非编码 RNA（包括 microRNAs、长非编码 RNA 和环状 RNA）调节，这些非编码 RNA 调节途径中所有蛋白的表达。
目前，研究最多的 DDR 抑制剂是 PARP 抑制剂（PARPi），在卵巢癌和乳腺癌中取得了重要的结果。PARPi 是一类肿瘤不可知的药物，在其他部位（如结肠癌和前列腺癌）也显示出疗效，这些部位具有与基因组不稳定性相关的分子特征。这些抑制剂诱导细胞内 DNA 损伤的积累、细胞周期停滞、有丝分裂灾难和细胞凋亡。
本研究旨在提供生理和治疗压力下胶质母细胞瘤 DDR 途径的综合图像，重点关注非编码 RNA 的调节作用。DDR 抑制剂作为基因组不稳定和 DDR 途径改变的肿瘤的一种重要新治疗方法正在出现。目前正在进行 PARPi 在 GBM 中的首次临床试验，并将在本文中介绍。此外，我们认为，通过将 DDR 途径中的调节网络纳入 GBM，我们可以填补以前试图有效靶向脑肿瘤时所存在的空白。本文介绍了非编码 RNA 在 GBM 和 DDR 生理学中的重要性及其相互关系。
