PARP inhibitors in gliomas: Mechanisms of action, current trends and future perspectives.

in Cancer treatment reviews by Eugenia Cella, Alberto Bosio, Pasquale Persico, Mario Caccese, Marta Padovan, Agnese Losurdo, Marta Maccari, Giulia Cerretti, Tamara Ius, Giuseppe Minniti, Ahmed Idbaih, Nader Sanai, Michael Weller, Matthias Preusser, Matteo Simonelli, Giuseppe Lombardi

TLDR

  • The study is about using a drug called PARP inhibitor (PARPi) to treat a type of brain tumor called glioma. The study compares the outcomes of using PARPi alone and in combination with other drugs. The results show that PARPi can help improve the prognosis of glioma, but there are challenges in using it, such as identifying the right patients, figuring out how to use it with other drugs, and managing side effects. The study suggests that more research is needed to confirm these findings and to develop new ways to use PARPi to treat glioma.

Abstract

Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and genomic stability and PARP inhibition (PARPi) may be a promising therapeutic approach for gliomas. Inhibition of PARP activity leads to homologous recombination deficiency (HRD), which, in combination with DNA damage, results in cell death. This review summarises the current knowledge and future perspectives of PARPi in glioma. The available literature was reviewed using PubMed, recent major international oncology congresses were consulted, and ongoing clinical trials were searched using ClinicalTrials.gov. In translational research, PARPi have demonstrated a strong scientific rationale for their use in the treatment of glioma. They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma. Most studies were open-label, non-randomised, dose-escalation phase I-II trials. Early results show promising anti-tumour activity, and key challenges include identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity. In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored.

Overview

  • The study focuses on the potential of PARP inhibition (PARPi) as a therapeutic approach for gliomas, the most common primary malignant brain tumors in adults. The hypothesis being tested is whether PARPi can improve the prognosis of gliomas. The methodology used for the experiment includes a review of the available literature using PubMed, recent major international oncology congresses, and ClinicalTrials.gov. The study aims to provide a summary of the current knowledge and future perspectives of PARPi in glioma treatment. The primary objective is to evaluate the scientific rationale for the use of PARPi in glioma treatment and to identify key challenges in its implementation. The study is an open-label, non-randomized, dose-escalation phase I-II trial.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, including PARPi alone and in combination with other drugs such as radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy, and other new drugs. The results show promising anti-tumor activity of PARPi, with early studies demonstrating its potential to improve the prognosis of gliomas. However, the study identifies key challenges in the implementation of PARPi, such as identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity.

Implications and Future Directions

  • The study's findings suggest that PARPi has the potential to improve the prognosis of gliomas, and future research should focus on confirming these findings in larger, prospective, and randomized trials. The development of novel PARPi with improved blood-brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored. The study also highlights the need to identify predictive biomarkers, elucidate synergistic effects in combination therapies, address the development of resistance, and manage hematological toxicity.
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