Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance

Abstract

Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.

RAD51 Inhibitor and Radiation Toxicity in Vestibular Schwannoma

“…When VS is treated with SRS, the goal is to maximize tumor control while minimizing toxicity to essential anatomic structures, such as the facial nerve, trigeminal nerve, and cochlea. Although retrospective investigations have shown that single fraction radiation with Gamma Knife SRS (marginal tumor dose, ~11-13 Gy) is associated with tumor control rates of 84% to 94% in VS, [12][13][14][15] facial nerve palsy occurs in approximately ~1% of patients, and progression to unserviceable hearing occurs in roughly 75% at 10 years. 10,[29][30][31][32][33] Thus, introduction of radiosensitizers such as RI-1 may improve tumor control rates and/or permit lower dosages of radiation with equivalent tumor control and less toxicity to adjacent neurovascular structures.…”

“…The exact mechanisms of radiation resistance of VS in patients are largely unknown but are likely related to several factors: (1) insufficient radiation dosages to initiate cell death, (2) efficient DNA repair systems, (3) tumor hypoxia preventing generation of radiation-induced reactive oxygen species, (4) altered expression of tumor suppressor and proto-oncogenes, (5) aberrant expression of cell cycle checkpoint proteins, (6) cumulative effects of the loss of function of the NF2-merlin tumor suppressor on cell proliferation, and (7) prolonged cell cycle arrest for DNA repair. 12,16,23-26 In our previous study, we showed that radioresistant VS cells mount a strong p21 response after radiation exposure (18 Gy), which can direct cells into cell cycle arrest and allow time for RAD51-associated repair of DNA damage. 21…”

“…Notably, the progression-free survival rate after SRS is approximately 84% to 94%. 10-15 However, a subset of VS does not respond to SRS and continues to grow. 13,14 The exact mechanisms behind this radiation resistance are poorly understood.…”

“…However, a subset of VS does not respond to SRS and continues to grow 13,14 . The exact mechanisms behind this radiation resistance are poorly understood 12,16 …”

Tantalum-carbon-integrated nanozymes as a nano-radiosensitizer for radiotherapy enhancement

“…However, in clinical practice, patients can develop different degrees of resistance to RT, leading to treatment failure and recurrence of metastasis, thus limiting the efficacy of RT for treatment of tumors ( Makhov et al, 2018 ). Addressing the sensitivity of RT has become a pivotal issue in the efficacy of RT in patients with tumors ( Huang and Zhou, 2020 ; Thielhelm et al, 2021 ; Li et al, 2022 ).…”