Understanding the mechanisms of transformation and hidden resistance of incurable haematological malignancies - PRIMA ANNUALITA'

The development of many blood cancers follows a highly protracted evolutionary process, beginning for many patients several years prior to the development of overt disease. Regardless, of the natural history of these malignancies, we typically treat patients once full-blown cancer has developed, where treatments are usually complex and expensive, with low cure rate, all of which contributes to a physical and psychosocial burden for the patients and their families at great societal economic impact. Further, despite the efficacy of current therapies, in a significant number of patients we are capable of identifying small populations of tumour cells, named minimal residual disease (MRD), being a reservoir of chemoresistant disease that eventually will lead to the relapse of the disease. Treatment in many cases is defer until clinical relapse of the disease. At odds with the approaches used today, we are postulating that blood cancers may be at their most vulnerable during their pre-malignant and MRD phases. Thus, therapeutic intervention at these time-points may ultimately provide our best opportunity in delivering a step change towards more effective disease control, improved long-term survival and potentially cure. To address this question we will focus on three groups of haematological malignancies that share similar models of cancer progression, from benign into malignant and lethal stages, and represent a large European population with unmet medical needs (up to 100,000 new patients are expected in Europe each year): 1. Monoclonal gammopathies (multiple myeloma -MM- and systemic light-chain amyloidosis -AL-); 2. Myeloid malignancies (myelodysplastic syndromes -MDS- and acute myeloid leukaemia -AML-); and 3. follicular lymphoma (FL). As outputs of the accelerator we expect to: 1) Identify precise biomarkers of early transformation and novel targets for pre-emptive treatment; 2) Understand and overcome the mechanism of initial MRD resistance and eventually relapsing disease. Our proposal is supported by: i) access to very large clinical cohorts of patients and samples; ii) the expertise of our team on novel technologies, next generation biomarkers and patient´s care; iii) our leadership in the standardisation of protocols (both for new methodologies and therapeutics; iv) we have recognised and appropriately resourced the major computational challenge that underpins this programme, which will be led by world leaders in clinical systems biology. Thus, as a consequence of this Accelerator Award we will provide tools for the global research community to treat disease causation instead of symptomatology and to tailor and manage initial chemoresistance instead of waiting for clinical relapses.