Periodic Reporting for period 1 - PREVALUNG EU (Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception.)
Reporting period: 2022-12-01 to 2023-11-30
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.
We suggest to estimate LC risk of CVD patients by assessing parameters relevant to metabolism, immunity, hematopoiesis and/or intestinal barrier fitness and to feed the results of this equation into rational intervention strategies designed to suppress pro-carcinogenic inflammation.
Based on this premise, several members of this consortium brought up the first proof-of-concept of the relevance of host-derived factors (as opposed to cell autonomous parameters) to predict health to disease transition, meaning early lung carcinogenesis in the context of CVD-related chronic systemic inflammation. We conducted a prospective observational study (i.e “PREVALUNG” NCT03976804) using the system biology approach to find omics-based predictors of LC incidence in a population of CVD-affected individuals. Patients from the PREVALUNG study displayed stabilized CVD and secondary prevention, LC remaining the major avoidable cause of death in this population.
According to our PREVALUNG EU vision, two specific aims will be harnessed within 5 years:
• Validate in both retrospective biobanks and large prospective cohorts, classifiers representing four functional drivers of chronic inflammation detecting CVD individuals pre-symptomatic and at early stages of lung carcinogenesis: this will allow to implement patient stratification for preventive interventions based on dysmetabolism, innate immunosuppression, clonal hematopoiesis or gut microbiota dysbiosis (4 main drivers).
• Demonstrate the actionability of such biomarkers: develop and test specific interceptive measures for each of the 4 main drivers of inflammation using food supplements or pharmacological agents (on the top of diet and lifestyle modifications) to return to homeostasis
These aims are splitted into five main objectives: 1/ To validate host classifiers of high-risk LC in CVD tobacco users, 2/ To develop and validate friendly user- tools for each of the four classifiers predicting the risk of developing LC in the near future, 3/ To demonstrate the actionability of the biomarkers developed through a randomized evaluation of targeted interceptive measures for each of the 4 main drivers, 4/ To allow the implementation and pharmacodynamic monitoring of the interceptive interventions deployed across European centers using PREVALUNG EU-Focus panels, and 5/ To evaluate implementation of the tools, efficacy of the interception measures, and propose a business case for the wider use of the classifiers and food supplements/drugs.
We suggest to estimate LC risk of CVD patients by assessing parameters relevant to metabolism, immunity, hematopoiesis and/or intestinal barrier fitness and to feed the results of this equation into rational intervention strategies designed to suppress pro-carcinogenic inflammation.
Based on this premise, several members of this consortium brought up the first proof-of-concept of the relevance of host-derived factors (as opposed to cell autonomous parameters) to predict health to disease transition, meaning early lung carcinogenesis in the context of CVD-related chronic systemic inflammation. We conducted a prospective observational study (i.e “PREVALUNG” NCT03976804) using the system biology approach to find omics-based predictors of LC incidence in a population of CVD-affected individuals. Patients from the PREVALUNG study displayed stabilized CVD and secondary prevention, LC remaining the major avoidable cause of death in this population.
According to our PREVALUNG EU vision, two specific aims will be harnessed within 5 years:
• Validate in both retrospective biobanks and large prospective cohorts, classifiers representing four functional drivers of chronic inflammation detecting CVD individuals pre-symptomatic and at early stages of lung carcinogenesis: this will allow to implement patient stratification for preventive interventions based on dysmetabolism, innate immunosuppression, clonal hematopoiesis or gut microbiota dysbiosis (4 main drivers).
• Demonstrate the actionability of such biomarkers: develop and test specific interceptive measures for each of the 4 main drivers of inflammation using food supplements or pharmacological agents (on the top of diet and lifestyle modifications) to return to homeostasis
These aims are splitted into five main objectives: 1/ To validate host classifiers of high-risk LC in CVD tobacco users, 2/ To develop and validate friendly user- tools for each of the four classifiers predicting the risk of developing LC in the near future, 3/ To demonstrate the actionability of the biomarkers developed through a randomized evaluation of targeted interceptive measures for each of the 4 main drivers, 4/ To allow the implementation and pharmacodynamic monitoring of the interceptive interventions deployed across European centers using PREVALUNG EU-Focus panels, and 5/ To evaluate implementation of the tools, efficacy of the interception measures, and propose a business case for the wider use of the classifiers and food supplements/drugs.
This consortium unveiled 33 biological parameters from the soluble plasmatic monitoring that predicted the event of “early carcinogenesis”. To corroborate these findings and validate their clinical relevance, a consortium member, KU LEUVEN, provided a Flemish cohort, composed of 38 lung cancers who were paired with 52 healthy controls and 64 CVD patients suffering from cardiovascular disease but cancer-free. FLEMENGHO (the Flemish Study on Environment, Genes and Health Outcomes cohort, KULeuven) is a large family-based population resource on the genetic epidemiology of cardiovascular phenotypes for which recruitment started in 1985 and continued through 2010. Interestingly, FLEMENGHO patients did not have cancer when they were sampled, which allowed to monitor the hits that correlate best with time to cancer. We performed the proteomics, the immunomics, inflammomics and the metabolomics and find about 48.8% hits (24 biological parameters) associated with lung cancers in common with PREVALUNG. When clustering cancer and cancer-free patients from the PREVALUNG and FLEMENGHO cohorts, we observed two significant clusters that contained most if not all cancer patients, clearly separated from the cancer-free individuals. The risk-associated pathways shared by both cohorts included cumulative alterations encompassing neutrophil and monocyte activation, IL-1b/IL-1R1 (associated with clonal hematopoiesis), Th2 immunity, gut barrier inflammation, as well as glucose, lipid and polyamine metabolism. Cancer risk to overt disease transition stems from cumulative failures of functional pathways amenable to combined interceptive strategies.
Ideally, cancer screening should be minimally invasive, low cost, provide minimal false negatives or false positives to minimize harm and maximize benefits. It should lead to interceptive measures that reduce cancer-specific incidence and mortality. Two key challenges are that oncological abnormalities are present at extremely low concentrations in very early-stage cancer and that most current proposed tests (imaging technologies, cfDNA, VOC, exosomes…) fail to lead to personalized interceptive therapies at this level. We are in need of functional biomarkers of chronic disorders preceding oncogenesis and pre-symptomatic early detection of cancer.
Our approach mostly relies on pre-established, and newly reported fingerprints obtained from cohorts of patients diagnosed with advanced malignancies or presymptomatic LC (unpublished data on the PREVALUNG cohort). Four major fingerprints (relying on dysmetabolism, dysbiosis, CHIP, maladaptive immunity) correlating with uncontrolled inflammation were unveiled in CVD tobacco users. They were based on high dimensional unbiased multi-omics technologies, integrating a holistic understanding of complex and intricated biological pathways involved in the transition of CVD to LC. These biological signatures permit a comprehensive, efficient and personalized prediction of the health status trajectory and are drug/food supplement targetable. Our multimodal data and biology-stratified approach goes beyond the state-of-the-art on multiple aspects, which can be:
(i) develop new LC high risk identification tools adjusted on the PLCOm2012 score of each individual, in order to improve the level of detection (ii) rely on host pathological pathways that should be drug or food supplement targetable, beyond tobacco use control and lifestyle changes (iii) adapt and personalize our interceptive measures to these new tools.
Indeed, our project proposes complementary and actionable tools i.e. biological fingerprints of inflammatory and immune drivers for the early detection of “high-risk” individuals in the scope of CVD. Our program is based on the detection of systemic (as opposed to local) inflammatory drivers of CVD leading to LC. Our approach is complementary from the cell autonomous, cancer-related genetic and epigenetic-based markers in that it takes into account the holistic deregulation of the host. Nevertheless, our UK partner (NHS North Central London “Targeted Lung Health Check” [NCL TLHC]) will analyze cfDNA technology in parallel to our classifiers.
Our approach mostly relies on pre-established, and newly reported fingerprints obtained from cohorts of patients diagnosed with advanced malignancies or presymptomatic LC (unpublished data on the PREVALUNG cohort). Four major fingerprints (relying on dysmetabolism, dysbiosis, CHIP, maladaptive immunity) correlating with uncontrolled inflammation were unveiled in CVD tobacco users. They were based on high dimensional unbiased multi-omics technologies, integrating a holistic understanding of complex and intricated biological pathways involved in the transition of CVD to LC. These biological signatures permit a comprehensive, efficient and personalized prediction of the health status trajectory and are drug/food supplement targetable. Our multimodal data and biology-stratified approach goes beyond the state-of-the-art on multiple aspects, which can be:
(i) develop new LC high risk identification tools adjusted on the PLCOm2012 score of each individual, in order to improve the level of detection (ii) rely on host pathological pathways that should be drug or food supplement targetable, beyond tobacco use control and lifestyle changes (iii) adapt and personalize our interceptive measures to these new tools.
Indeed, our project proposes complementary and actionable tools i.e. biological fingerprints of inflammatory and immune drivers for the early detection of “high-risk” individuals in the scope of CVD. Our program is based on the detection of systemic (as opposed to local) inflammatory drivers of CVD leading to LC. Our approach is complementary from the cell autonomous, cancer-related genetic and epigenetic-based markers in that it takes into account the holistic deregulation of the host. Nevertheless, our UK partner (NHS North Central London “Targeted Lung Health Check” [NCL TLHC]) will analyze cfDNA technology in parallel to our classifiers.