Title: Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable haematological malignancies
Funder: Cancer Research UK

Abstract: Background Although great strides have been made in the management of haematological malignancies in the last decade, our best opportunity to eradicate cancer lies in preventing progression at pre-malignant and minimal residual disease (MRD) states, and offers an under explored area for disease control and cure. Our accelerator consists of national hubs with a common vision around early intervention in 3 haematological disorders: Monoclonal Gammopathies (MG,Spain), Myelodysplastic syndromes & Acute Myeloid Leukaemia (MDS, AML- Italy), and Follicular Lymphoma (FL-UK), malignancies. The fact that these cancers share common singular models of cancer progression, from pre-malignant (clonal yet benign) into malignant disease (chemosensitive that ultimately become refractory due to persistent MRD) offers an unique opportunity for developing integrative models in which tumor clonal evolution, microenvironment and inmuno-editing will be simultaneously investigated, providing an opportunity to tease apart the commonalities and demarcations across the different states of disease. Aims and Methods The programme will be delivered across 5 research work packages (WPs) aimed at • Identifying precise biomarkers of early transformation and novel targets for pre-emptive treatment through comprehensive phenotypic and molecular analyses of single tumour cells versus their normal counterparts and corresponding immune cells from patients at different disease states (WP 1-2). • Overcoming initial tumour resistance by investigating the molecular nature of MRD clones, develop biomarkers for precision treatment based on MRD-immune signatures, and define surrogates of cure based on depth of MRD response and immune signatures (WP 3-4). followed by the integration of new data and medical information through a computational systems biology package (WP5) capable of identifying novel molecular signatures that predict the transition between different stages of disease and reveal new therapeutic opportunities. Dissemination and Management of the project will be addressed through WP6 and WP7. A total of 13 centres will participate in the project with availability of large number of samples and the technical expertise using state of the art technologies such as single cell RNA-seq, ATAC-seq and exome and cell free DNA sequencing or Next generation Flow. Impact The accelerator will bring us closer to a paradigm shift in the treatment of these three blood cancer groups, focussing on treating disease causation instead of symptomatology and an ability to tailor and manage MRD clones instead of waiting for invariable clinical relapses. To widen the impact, all the results as soon as available will be shared with the scientific community, cancer research charities and patient organizations.

Lay abstract: Background Although great strides have been made in the management of haematological malignancies in the last decade, our best opportunity to eradicate cancer lies in preventing progression at pre-malignant and minimal residual disease (MRD) states, and offers an under explored area for disease control and cure. Our accelerator consists of national hubs with a common vision around early intervention in 3 haematological disorders: Monoclonal Gammopathies (MG,Spain), Myelodysplastic syndromes & Acute Myeloid Leukaemia (MDS, AML- Italy), and Follicular Lymphoma (FL-UK), malignancies. The fact that these cancers share common singular models of cancer progression, from pre-malignant (clonal yet benign) into malignant disease (chemosensitive that ultimately become refractory due to persistent MRD) offers an unique opportunity for developing integrative models in which tumor clonal evolution, microenvironment and inmuno-editing will be simultaneously investigated, providing an opportunity to tease apart the commonalities and demarcations across the different states of disease. Aims and Methods The programme will be delivered across 5 research work packages (WPs) aimed at • Identifying precise biomarkers of early transformation and novel targets for pre-emptive treatment through comprehensive phenotypic and molecular analyses of single tumour cells versus their normal counterparts and corresponding immune cells from patients at different disease states (WP 1-2). • Overcoming initial tumour resistance by investigating the molecular nature of MRD clones, develop biomarkers for precision treatment based on MRD-immune signatures, and define surrogates of cure based on depth of MRD response and immune signatures (WP 3-4). followed by the integration of new data and medical information through a computational systems biology package (WP5) capable of identifying novel molecular signatures that predict the transition between different stages of disease and reveal new therapeutic opportunities. Dissemination and Management of the project will be addressed through WP6 and WP7. A total of 13 centres will participate in the project with availability of large number of samples and the technical expertise using state of the art technologies such as single cell RNA-seq, ATAC-seq and exome and cell free DNA sequencing or Next generation Flow. Impact The accelerator will bring us closer to a paradigm shift in the treatment of these three blood cancer groups, focussing on treating disease causation instead of symptomatology and an ability to tailor and manage MRD clones instead of waiting for invariable clinical relapses. To widen the impact, all the results as soon as available will be shared with the scientific community, cancer research charities and patient organizations.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS