Invasive fungal infections are an underestimated health problem, which is exacerbated by their difficult diagnosis and an increasing emergence of resistances to the few antifungals currently in use. Among the most common fungi in France and Germany causing systemic mycoses with high mortality rates are the yeast Candida albicans and the mould Aspergillus fumigatus. However, species such as Candida glabrata and Candida auris are emerging as increasingly important pathogens, not the least due to their intrinsic and acquired resistances to antifungals. Despite these problems, antifungal resistance surveillance especially in Germany is often still lacking. This project aims to obtain a more complete picture of the current distribution of resistance to the clinically used antifungals and, importantly, to screen a natural compound library for new leads towards novel antifungals. Notably, the screening will not be based only on fungistatic or fungicidal effects, but rather on the ability of the candidate compound to inhibit fungal virulence. This novel approach, targeting the actual detrimental activity rather than the growth, will significantly limit the selection pressure for the development of resistances. Complementing this approach, a targeted antifungal screening for kinase inhibitors will be performed, as these enzymes have emerged as promising targets in antiinfective research. To further ensure the effectiveness of a future drug based on these leads, representative populations of German and French clinical isolates of yeasts and moulds will be pre-emptively screened for possible pre-existing resistances, and for possible synergism with the frequently used azole drugs. Finally, the mode of action of the most promising lead candidates will be initially characterized by an unbiased, large-scale chemogenetic, proteomics and transcriptomics-based screen on the German side, and a complementary, highly targeted and systematic assay of stress response and signal transduction-related mutants on the French side. Continuous exchange of data, material and knowledge among the clinically and basic science-oriented partners in France and Germany, will guarantee an effective workflow toward the characterization of new, urgently sought antifungal lead compounds.

Diffuse large B-cell lymphoma is a heterogeneous disease, 30-40% of all patients failing induction therapy, with limited success of next-line regimens. Among several pathological and genetic features, deregulation of the MYC and BCL2 oncogenes is a strong predictor of negative prognosis: indeed, overexpression of their protein products - routinely assayed by immunohistochemistry - allows detection of “double-expresser” lymphomas (DEL), representing a sizeable patient population with an acute unmet medical need. Classically, personalized medicine approaches would either aim at identifying actionable lesions at relapse, or utilize information available at diagnosis to expand the induction regimen with targeted therapy. Here, we propose to “re-think” personalized medicine with an innovative phase I/II trial, aimed at eradicating minimal residual disease (MRD) in DEL patients following a clinical response to induction immune-chemotherapy. Toward this aim, we will use a targeted drug combination (Venetoclax and Tigecycline, or V/T) with demonstrated efficacy against BCL2/MYC DEL cells. At the various stages, liquid biopsies will be used to assess the presence of MRD, as well as to establish full mutational and expression profiles, thus allowing us to decipher a posteriori the molecular underpinnings that characterize responders and non-responders. This will be complemented with a systemetic effort to optimize health care by defining conceptually novel stratification criteria for the V/T consolidation regimen, exemplifying a fundamentally novel route into personalized medicine in the clinic. Finally, our clinical activities will be complemented by a focused pre-clinical research plan, in which mouse models that recapitulate high-risk DLBCL subsets will be subject to similar sequential regimens, thereby addressing the mechanisms of action of the relevant drugs, as well as the functional implications of defined mutational and transcriptional profiles.