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)是导致死亡的主要原因，与代谢重编程、不确定潜能克隆性造血(CHIP)、肠道生物失调和适应性免疫不良相关的慢性炎症过程相互交织。易患心血管疾病的烟草使用者每年的LC发病率为1-2%。低剂量计算机断层扫描筛查程序可将LC死亡率降低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故障将有助于采取预防措施。基于代谢Metageno蛋白质免疫基因组学，我们在CVD烟草消费者中进行的PREVALUNG前瞻性研究揭示了导致早期癌症发生的四个驱动因素，可以利用这些生物标志物开创个性化拦截措施的先河。四个主要目标将由7个学术合作伙伴(跨学科和截取试验人员)、3个诊断生物技术企业和1个营养基金会来实现。首先，在回顾和前瞻性队列(&gt；60.000)中，提炼和验证这4个分类器依赖于4个炎症驱动因素(自噬/先天免疫/肠道屏障缺陷和芯片)来实施患者分层。第二，开发和验证用于常规风险评估的监测此类生物标记物的强大、用户友好的工具。第三，通过一项生物知情的多臂随机试验，证明这些生物标志物的可操作性。除了饮食和生活方式的改变外，还可以使用食品补充剂或药物(分别是二甲双胍、抗NKG2A/PDL-1抗体、IL-1抑制剂、益生菌)针对四种主要炎症驱动因素中的每一种进行测试，以恢复体内平衡。第四，使患者和使用这些新工具的临床研究人员之间的安全接口适用于对拦截措施的纵向监测。

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.