Location: Campus Drie Eiken, Aula Fernand Nédée, D.Q.001

Time: 13u - 16u

Speakers:

1. Matthias Bosman
Arterial stiffness is transient during doxorubicin treatment despite persistent endothelial dysfunction: a longitudinal study complemented by proteomics
Aims: The chemotherapeutic doxorubicin (DOX) induces vascular toxicity, which is clinically relevant in cancer survivors since arterial stiffness and endothelial cell (EC) dysfunction are strong and independent markers for future cardiovascular risk. However, clinical studies have reported conflicting results regarding the impact of DOX treatment on vascular function. Accordingly, we aimed to longitudinally evaluate vascular function in a DOX-treated murine model complemented by a proteomics approach.​Methods and Results: Mice were injected intraperitoneally with vehicle or DOX (4 mg/kg/week) for 6 weeks with follow-up until 15 weeks. Arterial stiffness and vascular function were evaluated longitudinally in vivo and ex vivo. In addition, proteomics was performed to identify potential novel biomarkers. DOX increased arterial stiffness after 1 and 2 weeks and recovered shortly thereafter. However, EC dysfunction persisted during treatment, as evidenced by impaired endothelium-dependent acetylcholine-induced relaxation, decreased basal nitric oxide index and reduced phosphorylation of Ser1177-endothelial nitric oxide synthase. During follow-up, both arterial stiffness and EC dysfunction recovered. Finally, proteomics revealed higher levels of thrombospondin-1 and serpina3, two promising markers.​Conclusions: During treatment, DOX induces a transient increase in arterial stiffness despite persistent EC dysfunction, placing arterial stiffness as a time-sensitive and variable parameter. Thrombospondin-1 and serpina3 hold potential as promising markers in cardiovascular risk stratification, yet requires further clinical validation.

​2. Verdi Vanreusel
Towards two-dimensional in-vivo dosimetry for electron FLASH radiotherapy
Over 50% of all cancer patients receive radiation therapy as part of their treatment. However, the efficacy of this treatment is limited by the normal tissue toxicity  of the surrounding normal tissue. The last decade, a novel irradiation technique has been introduced that has the potential to revolutionize the field. Pre-clinical studies have shown the existence of the FLASH-effect, where a combination of ultra-high dose rates (UHDRs) and very short treatment times leads to a strong reduction of the normal tissue toxicity while preserving the anti-tumoural effect. Despite the revolutionary character of such a treatment, clinical implementation is hampered by the lack of accurate dosimetry at such high DR. The lack of dosimetry also prevents radiobiologists to understand the biological mechanisms underlying the FLASH-effect. In this study we investigate the potential of  2 dimensional dosimeters in UHDR electron beams. The 2D character allows their use for quality assurance of both the beam and the individual treatment. In 2020, the Iridium Netwerk has purchased the second in the world ElectronFlash linac (S.I.T.). This electron linac dedicated for preclinical FLASH research allows to vary all the important beam parameters considered important to obtain the FLASH-effect in a systematic way. It can vary 1) the dose via the number of pulses; 2) the dose per pulse via the amplitude of the pulse and the pulse length; and 3) the average dose rate with the pulse repetition frequency. It can generate electron beams with a nominal energy of 7 or 9 MeV. With 2D optically stimulated luminescent (OSL)- and 2D scintillating sheets, we investigated both a passive and a real time dosimeter, to be used as reference and in-vivo dosimeter respectively.For the OSL system we tested 2 sheets, which showed a linear response with dose (R²>0.99). No dose rate- and dose per pulse dependence could be observed for any of the sheets. Only one of the sheets showed no instantaneous dose rate dependence whereas the other showed decreased response for the higher instantaneous dose rate.  We also tested 3 scintillating sheets and we saw no dose per pulse dependence for any of the sheets. A dose rate dependence was observed, and was shown to be due to the decay time of the scintillating material. The sheets with sorter decay times were less dose rate dependent. Due to the short pulses associated with UHDR electron beams, the dead time of the camera becomes more relevant. We found that an the integration time should be set equal to the time between the pulses to exclude the effect of the dead time. A typical response map for both the OSL system and the scintillating system can be seen in Figure 1.We showed showed that the OSL system can be used for 2D reference dosimetry in UHDR electron beams, and that the scintillating system has the potential to be used as QA tool for in-vivo experiments. More investigation is needed on the synchronization of the integration time and start of the pulse to come to a reliable and robust technique.

3. Sanne van der Heijden - Center for Oncological Research (CORE)
Preclinical development and validation of a novel immunometabolic combination strategy for glioblastoma
Glioblastoma (GBM) is the most common malignant primary brain tumour. Responses to post-operative standard-of-care therapy are transient and tumors inevitably recur. Median survival is less then 15 months after diagnosis, with 5-year survival rates of less than 5%. Hence new effective treatment modalities represent a highly unmet need. Immunotherapy has generated remarkable clinical success in the past decade, in particular with immune checkpoint blockade (ICB), although to date not for GBM. Recent preclinical evidence has suggested that combination therapy can render GBM sensitive to ICB. Hence in this project, we investigate an immunometabolic therapy in murine GBM models in vivo as innovative treatment option. We aim to to metabolically reprogram the GBM tumour and its microenvironment to sensitize GBM to ICB immunotherapy. In our approach we mitigate the metabolic restraint on immune effector cells in the tumour by targeting the critical metabolic processes in GBM via pharmacological inhibition or dietary intervention. The resulting combination of tumour metabolic rewiring and ICB will be validated in top-end GBM mouse models to incorporate characteristics of human GBM. As such, our study holds great promise for clinical translation in patients with GBM.