Targeting HIF2α and PD-1 axes in clear cell renal cell carcinoma / The excess direct social cost of dementia-related neuropsychiatric symptoms: a beyond silos region-wide cohort study

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of kidney cancer, commonly characterized by somatic inactivation of the VHL gene. Loss of pVHL leads to stabilization of HIF1α and HIF2α, activating pathways involved in angiogenesis, cell cycle regulation and metabolism. HIF2α plays a central role in ccRCC oncogenesis, making it a promising therapeutic target. The pVHL/HIF2α axis also induces PD-L1 expression, suggesting a synergistic potential between HIF2α inhibitors and PD-1 immune checkpoint therapies. Clinical trials are evaluating this strategy, combining belzutifan (a HIF2α antagonist) with pembrolizumab (a PD-1 inhibitor). Our study investigated HIF2α inhibition and complete deletion in VHL-mutant and VHL-wt ccRCC cell lines and assessed the effect of belzutifan and pembrolizumab, either as monotherapy or in combination on the tumor microenvironment (TME) in patient-derived ccRCC models. Given the central role of metabolic reprogramming in ccRCC, we also developed a novel 3D-printed cell culture platform compatible with Raman spectroscopy measurements that enables real-time analysis of extracellular metabolites under controlled oxygen and nutrient gradients.

From a social perspective, the behavioral dimension of dementia is particularly significant because it affects mood and behavior through neuropsychiatric symptoms. These symptoms increase the economic burden and reduce the quality of life for both patients and caregivers. In this study, we examine the excess formal social costs (i.e. direct non-healthcare costs) associated with dementia-related neuropsychiatric symptoms, using region-wide population data Specifically, we analyze data on individuals aged 60 and older in Gipuzkoa. We apply two-part models, weighted using entropy balancing, to estimate formal social costs.

Our results indicate that the burden of caring for neuropsychiatric symptoms is greater than previously suggested in the literature. These symptoms more than triple the social costs of dementia due to increased use of residential care and formal coverage, reaching more patiens than earlier studies suggested. The higher prevalence of dementia and neuropsychiatric symptoms among individuals with lower socioeconomic status highlights a health inequality, partially mitigated by a greater use of social benefits. The talk will place special focus on the methodology used.