Abstract
Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.
Highlights
Radiotherapy (RT) plays a fundamental role in the treatment of patients with brain metastases and primary central nervous system (CNS) tumours, extending survival for many of these patients
PARP inhibitors (PARPi) utilized in clinical t and preclinical studies block the enzymatic function of poly(ADP-ribose) polymerase (PARP) by competing with its NAD+ substrate ip at the catalytic domain. This interferes with the DNA damage response (DDR) by suppressing base excision repair (BER) function and by cr preventing auto-modification of PARP delaying its release. This phenomenon of ‘PARP trapping’ s is increasingly recognized as playing a key mechanistic role in the therapeutic effects of PARPi, and u accounts for many of the differences observed between pharmacological inhibition and genetic n depletion of PARP.[20] a The aim of this review is to provide an overview of the physiological and clinical impact of M radiation-induced neuroinflammation and the specific role of PARP enzymes in this response
Using single cell RNAsequencing, researchers demonstrated that adult mice developed persistent microglial activation after brain irradiation, whereas juvenile mice (3 weeks old) exhibited an initial dynamic activation microglia that was followed by significant recovery after one week.[28,29]
Summary
Radiotherapy (RT) plays a fundamental role in the treatment of patients with brain metastases and primary central nervous system (CNS) tumours, extending survival for many of these patients.
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