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New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs

Published online by Cambridge University Press:  08 May 2023

Bianca Oana Pirlog ,
Silvina Ilut ,
Radu Pirlog ,
Paul Chiroi ,
Andreea Nutu ,
Delia Ioana Radutiu ,
George Daniel Cuc ,
Ioana Berindan-Neagoe ,
Seyed Fazel Nabavi  and
Rosanna Filosa
...Show all authors
Bianca Oana Pirlog
Affiliation:
Department of Neuroscience, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Silvina Ilut
Affiliation:
Department of Neuroscience, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Radu Pirlog*
Affiliation:
Research Center for Functional Genomics, Biomedicine and Translational Medicine, The “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Paul Chiroi
Affiliation:
Faculty of Medicine, University of Medicine and Pharmacology “Iuliu Hațieganu”, Cluj-Napoca, Romania
Andreea Nutu
Affiliation:
Faculty of Medicine, University of Medicine and Pharmacology “Iuliu Hațieganu”, Cluj-Napoca, Romania
Delia Ioana Radutiu
Affiliation:
Faculty of Medicine, University of Medicine and Pharmacology “Iuliu Hațieganu”, Cluj-Napoca, Romania
George Daniel Cuc
Affiliation:
Research Center for Functional Genomics, Biomedicine and Translational Medicine, The “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Ioana Berindan-Neagoe*
Affiliation:
Faculty of Medicine, University of Medicine and Pharmacology “Iuliu Hațieganu”, Cluj-Napoca, Romania
Seyed Fazel Nabavi
Affiliation:
Advanced Medical Pharma (AMP-Biotec), Biopharmaceutical Innovation Centre, Via Cortenocera, 82030, San Salvatore Telesino, BN, Italy Nutringredientes Research Center, Federal Institute of Education, Science and Technology (IFCE), Baturite, Ceara, Brazil
Rosanna Filosa
Affiliation:
Advanced Medical Pharma (AMP-Biotec), Biopharmaceutical Innovation Centre, Via Cortenocera, 82030, San Salvatore Telesino, BN, Italy Department of Science and Technology, University of Sannio, 82100, Benevento, Italy
Seyed Mohammad Nabavi
Affiliation:
Advanced Medical Pharma (AMP-Biotec), Biopharmaceutical Innovation Centre, Via Cortenocera, 82030, San Salvatore Telesino, BN, Italy Nutringredientes Research Center, Federal Institute of Education, Science and Technology (IFCE), Baturite, Ceara, Brazil
*
Corresponding authors: Radu Pirlog, Ioana Berindan-Neagoe, Seyed Mohamad Nabavi; Email: pirlog.radu@umfcluj.ro, ioana.neagoe@umfcluj.ro, nabavi208@gmail.com
Corresponding authors: Radu Pirlog, Ioana Berindan-Neagoe, Seyed Mohamad Nabavi; Email: pirlog.radu@umfcluj.ro, ioana.neagoe@umfcluj.ro, nabavi208@gmail.com
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

DNA damage responseGlioblastomanon-coding RNAsPARP inhibitorstargeted therapy
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 25 , 2023 , e18
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Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press

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Footnotes

*

These authors contributed equally to this work.

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