Hanne Verswyvel

Chapter 3 │ Page 99 [57-59]. Given that tumors can rapidly develop resistance to single-agent therapies, combining distinct treatment modalities may help to prevent or delay resistance occurring, ultimately improving therapeutic outcomes [60, 61]. As such, rationally designed combination strategies are increasingly recognized as the future of cancer treatment, o ering more e ective and durable responses compared to monotherapies. Building on our results in the spheroid model, we next validated our findings in patient-derived HNSCC-PDOs (Figure 3-4). This advanced in vitro model, often referred to as a “patient-in-the-lab”, provides an exceptional dimension toward clinical translation, as the model retains both the genotypic and phenotypic characteristics of the original tumor [62-64]. By maintaining these key features, PDOs allow for a more accurate prediction of clinical therapeutic responses within a laboratory setting [62, 65]. In our experimental design, we included an organoid from the oral cavity (HNSCC_001T) and one from the hypopharynx (HNSCC_007T). Both were derived from treatment-naïve patients, avoiding the confounding factor from prior therapies. Our results demonstrated a dose-dependent reduction in organoid viability for both NTP and CDDP, thereby confirming their cytotoxic potential in this translational model. In the HNSCC_001T organoid, the NTP-CDDP combination exhibited an added benefit, although not reaching full statistical significance. Future investigations should expand this analysis to a broader panel of patient-derived samples with diverse genetic and molecular backgrounds to assess the robustness and generalizability of the observed e ects. However, it is of note that growing organoids from patient samples and establishing it as a validated research model is a technically-demanding and time-consuming process with limited success rate, which also requires extensive coordination with the clinic. Once established, PDO cultures remain delicate and demand labor-intensive, tightly controlled culture conditions. A notable example of this hurdle is the frequent occurrence of

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