Valosin Containing Protein (VCP): Biomarker Of Radioresistance In Glioblastoma (Valor Study)

Background Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, char-acterized by poor prognosis and a high degree of therapeutic resistance. Despite ad-vances in surgery, radiotherapy, and temozolomide-based chemotherapy, median overall survival rarely exceeds 18 months. Radioresistance represents a major obstacle to effec-tive local control, often resulting from both intrinsic and adaptive cellular mechanisms. Among molecular mediators involved in DNA damage response (DDR) and protein homeostasis, the valosin-containing protein (VCP, also known as p97) has emerged as a potential regulator of cellular stress adaptation and repair processes. This study aimed to investigate the role of VCP as a marker of radioresistance in GBM, combining clini-cal and preclinical analyses to elucidate its association with treatment response and DNA repair efficiency. Materials and Methods The research was conducted in two complementary phases. In the retrospective clinical phase, VCP expression was evaluated by immunohistochemistry (IHC) on paraffin-embedded GBM samples from 25 patients treated with standard chemoradiation. Pa-tients were stratified into low- and high-VCP expression groups, and correlations with progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier and Cox proportional hazards analyses. In the preclinical ex vivo phase, 28 fresh-ly resected GBM tissues were exposed to graded radiation doses (0–8 Gy) to assess DNA damage and repair dynamics. Immunohistochemical quantification of γ-H2AX was used as a surrogate marker of double-strand breaks (DSBs), while VCP, GFAP, and CD45 expression were measured to characterize tumor composition and immune infil-tration. Results Clinically, a trend toward shorter PFS was observed in patients with high VCP expres-sion (median 9 vs 12 months; log-rank p = 0.59), consistent with a possible association between elevated VCP levels and enhanced radioresistance. No significant differences were found in OS. In multivariable models, MGMT promoter methylation—but not VCP—was independently associated with improved PFS. In the preclinical phase, γ-H2AX immunopositive area increased following irradiation, although this trend did not reach statistical significance, suggesting effective DNA damage induction across the an-alyzed specimens. Samples with higher baseline VCP expression tended to display lower residual γ-H2AX levels at 24 hours, supporting a potential, though not statistically sig-nificant, trend toward more efficient DNA damage resolution. Conclusion The present findings indicate that VCP may contribute to the intrinsic radioresistance phenotype of GBM, although the observed trends did not reach statistical significance within the current sample size. The integration of clinical and ex vivo data supports a functional link between VCP activity and DNA repair capacity. Future analyses on an expanded cohort of GBM specimens could aim to validate and refine these preliminary observations. In parallel, in vitro studies using GBM cell lines and selective VCP inhibi-tors could help to elucidate the mechanistic role of VCP in modulating cellular radio-sensitivity, potentially paving the way for novel translational approaches targeting VCP-mediated resistance pathways.