Objective Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health scienceshealth sciencespersonalized medicinemedical and health sciencesclinical medicinehematologymedical and health sciencesclinical medicineoncologyleukemia Keywords BCR-ABL JAK2 CML MPN bioinformatics modelling NRG xenograft tyrosine kinase inhibitors EZH2 p53 c-Myc bar-coding single cell precision medicine heterogeneity clonal evolution Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2016-ADG - ERC Advanced Grant Call for proposal ERC-2016-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution UNIVERSITY OF GLASGOW Net EU contribution € 2 856 679,00 Address UNIVERSITY AVENUE G12 8QQ Glasgow United Kingdom See on map Region Scotland West Central Scotland Glasgow City Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 856 679,00 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITY OF GLASGOW United Kingdom Net EU contribution € 2 856 679,00 Address UNIVERSITY AVENUE G12 8QQ Glasgow See on map Region Scotland West Central Scotland Glasgow City Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 856 679,00 THE UNIVERSITY OF MANCHESTER United Kingdom Net EU contribution € 149 138,75 Address OXFORD ROAD M13 9PL Manchester See on map Region North West (England) Greater Manchester Manchester Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 149 138,75