Controlling cell cycle, process by which cells progress and divide, is at the heart of cancer research therapies. Tumor cells signature often lays in high proliferation rate, alterations of multiple intracellular signaling networks and hijacking of programmed-cell death pathways. Implication of autophagy and lysosomal biology in cancer is still controversial. Lysosomes are catabolic vesicles involved in the degradation of biological material and need to be tightly regulated. Lysosomes may influence cancer formation and progression by regulating many complex processes of cell biology, such as cell signaling, cell death, nutrient sensing and cell metabolism. Lysosome function depends on lysosome acidification capacity modulated by proton pump v-ATPase activity and on its intracellular localization driven by motor proteins, mainly by motor protein kinesin KIF5B. We recently discover an innovative mechanism involving lysosomes impairment to induce mitotic error that could potentially lead tumor cells to cell death.

Implementation of next generation sequencing to genetic diagnosis and precision medicine has revolutionized the fields of hereditary cancer and oncology, increasing exponencially the identification of genetic variants of uncertain significance. Their classification is one of the most relevant and urgent challenges we face, since decision-making in the clinics depends on it. Evidence obtained from empirical functional studies is essential to reach a definitive classification; however, clinical relevance of such studies is currently low due to lack of standardized tests, use of inadequate models, and tediousness and cost- and time-inefficiency of available assays. Organ-VIP aims at surpassing the barriers we face when using and implementing functional assays for the interpretation of genetic variants in colorectal cancer (CRC) genes. State-of-the-art methodological and conceptual developments will facilitate the development of a screening platform to interpret the pathogenicity of variants in any CRC gene. To do so, we aim to: i) Use a model that faithfully represents the target tissue and genetic context (CRISPR/Cas9-edited human normal colon organoids); ii) Optimize end-point assay(s) to maximize performance, implementation, robustness and agreement with clinical evidence; iii) Assess genetic variants in hereditary CRC and polyposis genes; and iv) Calibrate the results for implementation in variant classifiers. Organ-VIP integrates clinical aspects, molecular and cell biology, next generation sequencing, and advanced bioinformatics analysis. The platform will not only be useful for variant interpretation in germline and somatic testing, but also for functional evaluation of new candidate CRC genes. In the longer term, Organ-VIP will become high-throughput by the implementation of saturation genome editing, high-throughput organoid culture, automation of sampling, and implementation of artificial intelligence.

IMPROVE will use Patient Generated Health Data (PGHD) gathered via m-health and e-health technologies to gain improved insights into the real-life behavior of, and challenges faced by, patients of all ages with complex, chronic diseases and comorbidities. Already today, a wealth of patient and citizen information is available, but fragmented, and therefore not coming to its full utility and value. These personal data will complement and improve existing approaches for Patient-Centered Outcome Measures beyond those currently available in state-of-the-art platforms. The IMPROVE platform that the consortium will build will enable the smart use of patient input and patient generated evidence to 1) advance the role of patient preference and patient experience in the context of treatment selection, 2) improve medical device design based on patient preferences and experiences, and 3) facilitate faster market entry of patient-centric and cost-effective advanced integrated care solutions. Improved clinical adoption of Value Based Health Care, and enhanced return on research and innovation investments will be demonstrated in different care settings across the EU, for 10 use cases in at least 5 different disease areas (e.g., ophthalmology, oncology, cardiovascular disease, chronic inflammation, and neurology). The use cases will be conducted using a large variety of implementation strategies, building on a design thinking approach, to optimally test the innovative framework of data gathering and translation into controlled change and action. In addition, a significant contribution from implementation science is planned to reach out to all stakeholders that are relevant for this initiative and maximise the impact to IMPROVE healthcare provision.

The Phosphoinositide 3-kinase (PI3K) pathway is at the core of multiple fundamental biological processes controlling metabolism, protein synthesis, cell growth, survival, and migration. This inevitably leads to the involvement of the PI3K signalling pathway in a number of different diseases, ranging from inflammation and diabetes to cancer, with PI3K pathway alterations present in almost 80% of human cancers. Therefore, PI3Ks have emerged as important targets for drug discovery and, during 2014, the first PI3K inhibitor was approved by FDA in the US for the treatment of a lymphocytic leukaemia. Nonetheless, our understanding of PI3K-mediated signalling is still poor and only a fraction of the potential therapeutic applications have been addressed so far, leaving a large amount of translational work unexplored. Europe features a set of top quality research institutions and pharmaceutical companies focused on PI3K studies but their activities have been so far scattered. This proposal fills this gap by providing a multidisciplinary network (biochemistry, mouse studies, disease models, drug development, software development) and an unprecedented training opportunity from the bench to the bedside (from pre-clinical discoveries to clinical trials), through cutting edge molecular biology, drug discovery and clinical trial organization. The proposal is aimed at training young investigators in deep understanding of the different PI3K isoforms in distinct tissues and to translate this knowledge into a new generation of PI3K inhibitors, treatment modalities and into identify new uses for existing PI3K inhibitors.