PREVALUNG EU - Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception

心血管疾病（CVD）和肺癌（LC）是死亡和与代谢重编程、不确定潜能的克隆造血（CHIP）、肠道生态失调和适应不良免疫相关的相互交织的慢性炎症过程的主要原因。CVD倾向的烟草使用者表现出每年1-2%的LC发病率。低剂量计算机断层扫描筛查计划降低LC死亡率20%。除了流行病学评分，风险识别、早期癌症检测和拦截大多基于细胞自主方法。了解将CVD与LC联系起来的病理生理学失败将允许采取预防措施。基于代谢-宏基因-蛋白-免疫基因组学，我们在CVD烟草消费者中进行的PREVALUNG前瞻性研究揭示了早期致癌的四个驱动因素，从而产生了可用于开创个性化拦截措施的可操作生物标志物。四个主要目标将由7个学术合作伙伴（跨学科和拦截试验），3个诊断生物技术中心和一个营养基金会利用。首先，在回顾性和前瞻性队列（>60.000）中完善和验证依赖于4种炎症驱动因素（自噬/先天免疫/肠屏障缺陷和CHIP）的4种分类器，以实现患者分层。其次，开发和验证强大的友好用户工具，监测这些生物标志物，用于常规风险评估。第三，通过一项生物信息多组随机试验证明这些生物标志物的作用，该试验使用食物补充剂或药物（分别为二甲双胍、抗NKG 2A/PDL-1抗体、IL-1抑制剂、益生菌）以及饮食和生活方式改变来测试针对炎症4个主要驱动因素中每一个的措施，以恢复体内平衡。第四，在患者和临床研究人员之间建立一个安全的接口，使用这些新工具对拦截措施进行纵向监测。

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.