Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception.

Cardiovascular disease (CVD) and lung cancer (LC) are leading causes of deaths and intertwined chronic inflammatory processes associated with metabolism reprogramming, clonal hematopoiesis of indeterminate potential (CHIP), intestinal dysbiosis, and maladaptive immunity. CVD prone-tobacco users exhibit a 1-2% yearly incidence of LC. Low dose computed tomography screening programs reduce LC mortality by 20%. Beyond epidemiological scores, risk identification, early cancer detection and interception are mostly based on cell autonomous approaches. Understanding pathophysiological failures linking CVD to LC would allow to take steps for prevention. Based on metabolo-metageno-proteo-immuno-gen-omics, our PREVALUNG prospective study conducted in CVD tobacco consumers allowed to unveil four drivers of early carcinogenesis leading to actionable biomarkers that can be harnessed to pioneer personalized interceptive measures. Four main objectives will be harnessed by 7 academic partners (transdisciplinarity and trialists in interception), 3 diagnostic Biotech Cies and one nutrition Foundation. First, refine and validate in retro- and pro-spective cohorts (>60.000), the 4 classifiers relying on the 4 inflammatory drivers (autophagy/innate immunity/intestinal barrier defects and CHIP) to implement patient stratification. Second, develop and validate robust friendly-user tools monitoring such biomarkers for routine risk assessment. Third, demonstrate the actionability of these biomarkers through a biologically-informed multi-arm randomised trial testing measures targeting each of the 4 main drivers of inflammation using food supplements or pharmacological agents (metformin, anti-NKG2A/PDL-1 Abs, IL-1 inhibitor, probiotics respectively) in addition to diet and life-style changes to return to homeostasis. Fourth, to adapt a secured interface between patients and clinical researchers using these new tools to the longitudinal monitoring of the interceptive measures.