Periodic Reporting for period 2 - INTERCEPT-MDS (Exploring cell-to-cell heterogeneity and exploiting epigenetic regulation for the interception of myeloid disease cells.)
Periodo di rendicontazione: 2023-01-01 al 2024-12-31
Promoting healthy aging is a global goal from the European Commission. Acute myeloid leukaemia (AML) is the most common type of acute leukaemia in adults and myelodysplastic syndrome (MDS) is the most frequent hematopoietic disorder of the elderly. Due to limited treatment options, the overall 5-year survival rate is less than 30%. These disorders remain among the most devastating cancers worldwide.
Disease interception is a novel concept referring to treatment of a disease before it fully develops by removing altered cells. Ideally, diseases could be intercepted and removed from the body during an asymptomatic stage of the disease, and the disease would never develop. However, the identification and specific targeting of diseased cells amongst a population of healthy cells without side effects remains a challenge. The EU-funded INTERCEPT-MDS project establishes a multidisciplinary training programme to provide early-stage researchers with the necessary expertise in the field. The project gathers pan-European experts and experienced trainers from two sectors (academia and industry) and two research environments (clinic and basic) to make this possible. Thus, INTERCEPT-MDS’ global goal is to promote healthy aging by approaching the disease cell interception, providing human capital, establish durable links between leading organisations and cross-fertilization between sectors. The project is expected to advance the field of disease interception and improve the clinical outcome of myeloid diseases.
From a scientific perspective, the project focuses on myeloid diseases and uses single-cell state-of-the-art methodologies to develop novel research tools that can help identify clonally distinct cells. INTERCEPT-MDS’ scientific questions and objectives are tackled by three independent but interconnected work packages (WP): WP1 – Identification of disease cells; WP2 - Exploring and exploiting epigenetics for interception; WP3 - Models and tools for disease cell detection and interception.
INTERCEPT-MDS’ training objectives are to: 1) train in state-of-the-art knowledge of myeloid diseases and epigenetic regulation to advance on the development of disease cell interception strategies; 2) transmit the skills to leverage latest technologies; 3) provide early-stage researchers with a toolset of transferable skills and a network of peers that will allow them to successfully develop their careers in any sector; 4) provide a personalized and tailored training maximizing individual career perspectives.
Disease interception is a novel concept referring to treatment of a disease before it fully develops by removing altered cells. Ideally, diseases could be intercepted and removed from the body during an asymptomatic stage of the disease, and the disease would never develop. However, the identification and specific targeting of diseased cells amongst a population of healthy cells without side effects remains a challenge. The EU-funded INTERCEPT-MDS project establishes a multidisciplinary training programme to provide early-stage researchers with the necessary expertise in the field. The project gathers pan-European experts and experienced trainers from two sectors (academia and industry) and two research environments (clinic and basic) to make this possible. Thus, INTERCEPT-MDS’ global goal is to promote healthy aging by approaching the disease cell interception, providing human capital, establish durable links between leading organisations and cross-fertilization between sectors. The project is expected to advance the field of disease interception and improve the clinical outcome of myeloid diseases.
From a scientific perspective, the project focuses on myeloid diseases and uses single-cell state-of-the-art methodologies to develop novel research tools that can help identify clonally distinct cells. INTERCEPT-MDS’ scientific questions and objectives are tackled by three independent but interconnected work packages (WP): WP1 – Identification of disease cells; WP2 - Exploring and exploiting epigenetics for interception; WP3 - Models and tools for disease cell detection and interception.
INTERCEPT-MDS’ training objectives are to: 1) train in state-of-the-art knowledge of myeloid diseases and epigenetic regulation to advance on the development of disease cell interception strategies; 2) transmit the skills to leverage latest technologies; 3) provide early-stage researchers with a toolset of transferable skills and a network of peers that will allow them to successfully develop their careers in any sector; 4) provide a personalized and tailored training maximizing individual career perspectives.
WP1 addresses the key challenge to identify disease cells at the earliest possible. The overall goal is to draw a timeline of the steps in the pathogenesis that will enable the In WP1, researchers developed robust model systems, including murine models and specialized cell lines, to understand the pathogenesis of myeloid diseases. They discovered the impact of specific mutations, such as STAG2 and CSNK1A1, on disease progression and therapy resistance. Using primary patient-derived samples and new methods like single-cell RNA sequencing and kinome activity profiling, they elucidated single-cell mechanisms affecting disease progress. Key findings included transcriptional changes and molecular mechanisms underlying STAG2 mutations, the impact of CSNK1A1 mutations on hematopoietic stem and progenitor cells, and the role of mesenchymal stromal cells from CHIP individuals in remodeling the progenitor cell compartment.
In WP2, the focus was on studying epigenetic regulators as potential drug targets for therapeutic intervention, aiming to intercept early disease cells. Researchers used advanced cellular and mouse models, as well as primary cells from MDS patients, to investigate the contribution of epigenetic regulation to MDS pathogenesis. They found that the interplay between progenitor cells and leukemic cells involves cell-specific pathways, with STAG2 playing a key role. They also identified druggable targets using CRISPR-Cas9, modeled the NUP98::KDM5A fusion protein, and tested amiodarone derivatives, finding a compound effective against NUP98::KDM5A-dependent cancer cells. Additionally, they developed methods for precise degradation of NUP98 fusion oncoproteins and identified new NUP98 fusions as potential treatment targets.
In WP3, the goal was to develop novel pre-clinical models and improved data analysis tools to accelerate research progress towards intercepting myeloid diseases. Researchers used 3D models to investigate aging effects, finding that aged-like human bone marrow niches enhance the proliferation and fitness of pre-leukemic MDS cells. They performed extensive genomics analyses on MDS patient samples, identifying novel VEXAS variants and developing methods to deconvolute gene expression profiles. They also optimized a Patient Derived Xenograft model for pre-clinical evaluation of new therapies, identifying potential therapeutic targets, and developed protocols to generate iPSC cells from MDS patient cells. Additionally, they created a bioinformatics pipeline to improve scRNA-Seq data analysis, detecting non-linear gene expression changes and capturing dynamic pathway shifts.
During the program, the ESRs kept on disseminating their results through posters and oral communications at conferences, and especially more actively close to the end of the project. The management team was compromised on following the dissemination strategy described in the section 2.3 of the Description of the Action, facilitating internal communication and maximizing external dissemination. Until today, the scientific WP leaders were closely monitoring the progress of ESRs but they have not identified results that might be exploitable and warrant protection
In WP2, the focus was on studying epigenetic regulators as potential drug targets for therapeutic intervention, aiming to intercept early disease cells. Researchers used advanced cellular and mouse models, as well as primary cells from MDS patients, to investigate the contribution of epigenetic regulation to MDS pathogenesis. They found that the interplay between progenitor cells and leukemic cells involves cell-specific pathways, with STAG2 playing a key role. They also identified druggable targets using CRISPR-Cas9, modeled the NUP98::KDM5A fusion protein, and tested amiodarone derivatives, finding a compound effective against NUP98::KDM5A-dependent cancer cells. Additionally, they developed methods for precise degradation of NUP98 fusion oncoproteins and identified new NUP98 fusions as potential treatment targets.
In WP3, the goal was to develop novel pre-clinical models and improved data analysis tools to accelerate research progress towards intercepting myeloid diseases. Researchers used 3D models to investigate aging effects, finding that aged-like human bone marrow niches enhance the proliferation and fitness of pre-leukemic MDS cells. They performed extensive genomics analyses on MDS patient samples, identifying novel VEXAS variants and developing methods to deconvolute gene expression profiles. They also optimized a Patient Derived Xenograft model for pre-clinical evaluation of new therapies, identifying potential therapeutic targets, and developed protocols to generate iPSC cells from MDS patient cells. Additionally, they created a bioinformatics pipeline to improve scRNA-Seq data analysis, detecting non-linear gene expression changes and capturing dynamic pathway shifts.
During the program, the ESRs kept on disseminating their results through posters and oral communications at conferences, and especially more actively close to the end of the project. The management team was compromised on following the dissemination strategy described in the section 2.3 of the Description of the Action, facilitating internal communication and maximizing external dissemination. Until today, the scientific WP leaders were closely monitoring the progress of ESRs but they have not identified results that might be exploitable and warrant protection
The INTERCEPT-MDS project is expected to advance the novel field of disease interception and improve the clinical outcome of myeloid diseases that remain among of the most devastating cancers worldwide. Disease interception refers to the removal of disease cells at the asymptomatic stage and before they expand and cause disease. If successful, this will have a significant societal impact, reducing the burden on patients and their families and increasing their quality of life. In addition, disease interception has the potential to change how we address the health challenges of the ageing population. Thus, at a European level, the socio-economic impact could also be substantial, lowering the high cost per patient and the disease incidence and contributing to improve the sustainability and efficiency of European healthcare systems. The tight collaboration between industry, clinic and basic research in INTERCEPT-MDS facilitates the transfer of knowledge and exploitation of the results. Importantly, the developed knowledge and tools in our projects are expected to be applicable to other diseases such as solid cancers.
By the end of the INTERCEPT-MDS funding period, we expect to have acquired novel insights into disease interception, have developed novel pre-clinical models and computational tools, have identified novel targets towards therapeutic applications and thus will have advanced on making disease cell interception a reality. Last an most importantly, we will have trained a new cohort of researchers, giving them the needed expertise and unique skills to further develop this exciting new field at the interface of basic research, health care and industry.
By the end of the INTERCEPT-MDS funding period, we expect to have acquired novel insights into disease interception, have developed novel pre-clinical models and computational tools, have identified novel targets towards therapeutic applications and thus will have advanced on making disease cell interception a reality. Last an most importantly, we will have trained a new cohort of researchers, giving them the needed expertise and unique skills to further develop this exciting new field at the interface of basic research, health care and industry.