Targeting cytomegalovirus in brain tumor therapy : from bench to bedside

<p dir="ltr"><b>Background</b></p><p dir="ltr">Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by rapid progression, poor therapeutic response, and dismal prognosis. Despite advances in molecular understanding, the standard of care has remained largely unchanged since the introduction of the Stupp protocol in 2005, which combines surgery, radiotherapy, and temozolomide chemotherapy. Most tumors are recurring within 7 months, and the median overall survival (OS) remains approximately 15 months. Currently, there is no consensus or approved standard treatment for recurrent GBM. This highlights an urgent need for novel therapeutic approaches and actionable targets in neuro-oncology to help these patients to a better future.</p><p dir="ltr"><b>Human Cytomegalovirus in GBM</b></p><p dir="ltr">The presence of human cytomegalovirus (HCMV) in GBM was first reported by Cobbs et al. in 2002, opening new perspectives in tumor biology and treatment. Our group and others have since then demonstrated that HCMV infects the vast majority (89-99%) of GBM and other central nervous system tumors, where it is proposed to play an essential oncomodulatory role. Although HCMV is not classified as an oncogenic virus, it possesses the capacity to induce several hallmarks of cancer. Importantly, its presence and expression levels in GBM have been associated with patient survival outcomes. Like other herpesviruses, HCMV establishes lifelong latency and evades immune clearance. Furthermore, it can be reactivated during radiotherapy, occasionally resulting in life-threatening encephalitis. These findings suggest that antiviral therapy targeting HCMV could be a promising adjunctive approach in GBM management.</p><p dir="ltr"><b>Aims</b></p><p dir="ltr">The overall aim of this PhD project was to explore the clinical and biological significance of HCMV in brain tumors, with a particular focus on its translational potential. The long-term objective is to develop innovative therapeutic strategies incorporating antiviral treatment into neuro-oncological clinical practice.</p><p dir="ltr"><b>Summary of Projects</b></p><p dir="ltr"><b>Project I-III: Retrospective Clinical Cohort Studies</b><br>In three retrospective studies, we analyzed survival outcomes in patients with (I) primary, (II) recurrent, and (III) secondary glioblastoma treated with the antiviral drug valganciclovir (VGCV) in addition to standard therapy at Karolinska University Hospital. Across all subgroups, patients who received VGCV demonstrated a trend toward longer survival compared to matched controls treated with standard therapy alone, suggesting a potential therapeutic benefit of antiviral intervention.</p><p dir="ltr"><br></p><p dir="ltr"><b>Project IV: HCMV Expression, Survival and Epilepsy</b> <br>We examined the association between HCMV infection and survival in a cohort of GBM patients with tumor-related epilepsy (TRE). Our findings indicate that high levels of HCMV proteins were correlated to Focal-to-bilateral tonic-clonic (FBTCS) and to shorter survival.</p><p dir="ltr"><br></p><p dir="ltr"><b>Project V: Mechanistic Insights into HCMV-Host Interactions</b> <br>We demonstrated that HCMV actively induces replication stress and DNA damage in host cells, creating a microenvironment favorable for viral gene expression. Simultaneously, HCMV hijacks the host stress response to upregulate its early gene expression. Simultaneously, HCMV hijacks the host stress response to upregulate its early gene expression. These findings suggest a feedback loop that may contribute both to tumor progression and viral persistence, providing a mechanistic rationale for antiviral therapy.</p><p dir="ltr"><br></p><p dir="ltr"><b>Project VI: Prospective Randomized Trial of VGCV</b><br>In a prospective, randomized, double-blind study, we investigated HCMV reactivation in GBM patients undergoing radio-chemotherapy. Patients receiving prophylactic VGCV experienced no HCMV reactivation, while nearly 40% of those in the placebo group showed viral reactivation, which was associated with significantly worse prognosis. These clinical observations were corroborated by in vitro studies in HCMV-infected GBM cell lines and in vivo in a murine model, further supporting the hypothesis that HCMV reactivation negatively affects treatment outcomes and that VGCV may mitigate this risk.</p><p dir="ltr"><br></p><p dir="ltr"><b>Conclusion</b></p><p dir="ltr">Collectively, this thesis supports a clinically significant role for HCMV in glioblastoma pathophysiology. Our findings indicate that antiviral therapy with VGCV may improve survival outcomes in both primary and recurrent GBM settings The mechanistic studies suggest that HCMV contributes to tumor progression by exploiting the host stress response and inducing replication stress. We also found that a higher degree of CMV infection is associated with a clinical phenotype of FBTCS and poor survival; future study should be done to understand if HCMV can promote directly epileptogenesis. Overall, these insights pave the way for future clinical trials and suggest that targeting HCMV could become a novel adjunct strategy in the multimodal treatment of GBM.</p><h3>List of scientific papers</h3><p dir="ltr">I. Stragliotto G*, <b>Pantalone MR</b>*, Rahbar A, Bartek J, Söderberg-Naucler C. Valganciclovir as Add-on to Standard Therapy in Glioblastoma Patients. Clin Cancer Res. 2020;26(15):4031-4039. *shared first authorship <a href="https://doi.org/10.1158/1078-0432.ccr-20-0369" rel="noreferrer" target="_blank">https://doi.org/10.1158/1078-0432.ccr-20-0369</a></p><p dir="ltr">II. <b>Pantalone MR</b>, Rahbar A, Söderberg-Naucler C, Stragliotto G. Valganciclovir as Add-on to Second-Line Therapy in Patients with Recurrent Glioblastoma. Cancers (Basel). 2022;14(8):1958. Published 2022 Apr 13. doi:10.3390/cancers14081958<br><a href="https://doi.org/10.3390/cancers14081958" rel="noreferrer" target="_blank">https://doi.org/10.3390/cancers14081958</a></p><p dir="ltr"><br></p><p dir="ltr">III. Stragliotto G*, <b>Pantalone MR</b>*, Rahbar A, Söderberg-Nauclér C. Valganciclovir as Add-On to Standard Therapy in Secondary Glioblastoma. Microorganisms. 2020;8(10):1471. Published 2020 Sep 24. I. *shared first authorship <a href="https://doi.org/10.3390/microorganisms8101471" rel="noreferrer" target="_blank">https://doi.org/10.3390/microorganisms8101471</a></p><p dir="ltr">IV. De la Cerda-Vargas MF, <b>Pantalone MR</b>, Söderberg Nauclér C, Medrano-Guzman R, Jauregui Renaud K, Nettel Rueda B, Reynoso- Sanchez MJ, Lopez-Quintana B, Rodriguez-Florido MA, Feria-Romero IA, Trejo-Rosales RR, Arreola-Rosales RL, Candelas-Rangel JA, Navarro-Dominguez P, Meza-Mata E, Muñoz-Hernandez MA, Segura- Lopez FK, Gonzalez-Martinez MDR, Delgado-Aguirre HA, Sandoval- Bonilla BA. Focal-to-bilateral tonic-clonic seizures and High-grade CMV-infection are poor survival predictors in Tumor-related Epilepsy Adult-type diffuse gliomas-A single-center study and literature review. Heliyon. 2024 Apr 2;10(7):e28555. <a href="https://doi.org/10.1016/j.heliyon.2024.e28555" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.heliyon.2024.e28555</a></p><p dir="ltr">V. Merchut-Maya JM, Bartek J Jr, Bartkova J, Galanos P, <b>Pantalone MR</b>, Lee M, Cui HL, Shilling PJ, Brøchner CB, Broholm H, Maya-Mendoza A, Söderberg-Naucler C, Bartek J. Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability. Cell Death Differ. 2022 Aug;29(8):1639-1653. <a href="https://doi.org/10.1038/s41418-022-00953-w" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41418-022-00953-w</a></p><p dir="ltr">VI. <b>Pantalone MR</b>, Stragliotto G, Martin-Almazan N, Lawler S, Bartek J, Söderberg-Naucler C Valganciclovir prevents Cytomegalovirus reactivationc upon chemoradiotheray in patients with Gliobalstoma. [Manuscript]</p>