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

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

Journal: Cancer treatment reviews 2024;131():102850

PMID: 39531943

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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.

Address: Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Internal Medicine and Medical Specialties (Di.M.I), University of Genoa, Genoa, Italy.; Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.; Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; Oncology Department, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy.; Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy.; Department of Radiation Oncology, Sant'Andrea Hospital, University of Rome Sapienza, Via Grottarossa 1035, 00189 Rome, Italy.; Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, DMU Neurosciences, Service de Neuro-Oncologie-Institut de Neurologie, F-75013 Paris, France.; Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.; Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerand.; Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.; Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: [email protected].

DOI: 10.1016/j.ctrv.2024.102850