Chronic kidney disease (CKD) is a progressive disease in which kidney function is gradually lost. It can develop consequent of many (kidney) diseases and it affects more than 10% of the world population. Although in recent years sodium–glucose cotransporter 2 inhibitors and novel non-steroidal mineralocorticoid antagonists are showing significant effects on CKD, the majority of patients treated still progress towards end-stage renal disease (ESRD). With dialysis or kidney transplantation as the sole treatments available in case of ESRD, the disease represents an enormous burden on healthcare costs throughout Europe. Caused by organ injury, fibrosis leads to replacement of functional tissue and organ architecture by extracellular matrix, leading to tissue scar formation and impaired function of the affected organ. This makes fibrosis a key therapeutic target to improve organ function in e.g., CKD. Myofibroblasts are the key driver cells of fibrosis across organs and research in our lab has demonstrated that targeting myofibroblasts stabilises organ function. Additionally, we have identified GLI1/2 as a myofibroblast cell-cycle progression-specific target. We found that the number of Gli proteins, transcriptional effectors of the Hedgehog signalling pathway, are significantly increased in the kidney after injury. Furthermore, GLI1/2 are ideal targets as they are not expressed during homeostasis in adults. DISRUPT-KF will validate a set of novel Gli inhibitors as disease-modifying drug candidates for CKD. Preliminary evidence shows anti-fibrotic efficacy in human 2D culture platforms and in induced pluripotent stem cell-derived kidney organoids in vitro. During DISRUPT-KF we will further verify and optimise the anti-fibrotic drug candidates in relevant in vitro (kidney fibrosis organoids) and in vivo (mice) models to validate their potential. We will also develop and execute an IP strategy and a commercial feasibility analysis to enter the anti-fibrotic CKD market.

Colorectal cancer (CRC), which includes cancers of the colon and rectum, represents a significant global health challenge as the third most commonly diagnosed and second most fatal cancer worldwide. It also places a substantial burden on European patients and healthcare systems. While standard treatments are available, they face significant limitations, especially in managing advanced CRC, often leading to poor patient outcomes and severely compromised quality of life. Emerging immunotherapies like immune checkpoint inhibitors (ICIs) and adoptive cell therapies show promise but face major obstacles, including high costs, side effects, lack of tumor targeting, and, most critically, they fail to treat "cold" CRC tumors with low or absent pre-existing anti-cancer immunity. Prof. Shi and his team have developed an innovative oral cancer vaccine to transform these “cold” CRC tumors into “hot” tumors by provoking potent cellular and humoral anti-cancer immunity. The vaccine will achieve this through its acid-stable nanovesicle structure to induce potent and intestine-localized anti-cancer immunity with reduced systemic side effects and improved patient compliance. This project aims to explore the technical and commercial potential of the vaccine platform.

Fibrosis is estimated to be involved in 45% of global mortality, and currently no specific therapies for fibrosis in most organs exist. One central and controversially discussed question in the field of organ fibrosis is: “is fibrosis truly reversible”? In Rewind-MF, I will address this biologically and clinically highly relevant question in a prime example: bone marrow fibrosis in a chronic blood cancer called Primary Myelofibrosis (PMF). In PMF, hematopoietic stem cells become mutated and activate fibrosis-driving cells. Fibrosis reversal in PMF is possible through allogeneic stem cell transplant (ASCT). However, the majority of patients are not eligible for this high-risk procedure. Alternative fibrosis-reversing strategies are not available, leaving this patient group without any treatment option. My specific aims in Rewind-MF are: (1) to gain spatio-temporal insights into fibrosis reversal and mutant clone elimination mechanisms to predict, which patients will benefit from ASCT, and to identify therapeutic targets; (2) to understand how blood cancer is maintained in the bone marrow and later the spleen stroma in order to find new ways to reverse fibrosis, and eradicate the cancer cells, and (3) to validate fibrosis reversal mechanisms and translate them into clinically relevant therapeutic strategies. What makes Rewind-MF unique is the holistic “bench-to-bedside” approach starting from a stem cell biological hypothesis [tested by innovative murine models and (stem) cell approaches], advanced by a broad interdisciplinary expertise with novel single cell, spatial genomic and computational technologies, to dissect mechanisms of fibrosis reversal and develop therapeutic approaches which go beyond pure target identification. The integration of all these technologies in clinically relevant specimens with follow-up data and large independent validation cohorts will truly revolutionize the prognostication and (personalized) treatment of patients with MF.

Immunotherapy holds great promise for curative cancer treatment. While immune checkpoint inhibitors can induce complete and long-term cures, the percentage of patients responding to immunotherapy remains to be low. Combining immunotherapy with chemotherapeutic drugs that induce immunogenic cell death (ICD) is among the most promising strategies to potentiate antitumor immune responses. Chemotherapeutics are clinically typically administered via intravenous infusion, once every couple of weeks, at high doses. Metronomic dosing is based on the application of chemotherapy drugs at high frequency and low doses, and it is gaining increasing interest to potentiate chemo-immunotherapy responses. However, high-frequency low-dose chemotherapy administration in the clinic via intravenous infusion is pragmatically undoable and economically not feasible. At-home administration via oral ingestion or subcutaneous self-injection is impossible, because of the side effect spectrum of chemotherapeutic drugs. In the PRIME project, we aim to establish PRodrug technology for Immunotherapy-priming via patient-friendly at-home MEtronomic dosing. Prodrugs have assisted in improving drug performance for over a century now, and they are widely employed in pharmaceutical industry and clinical practice, with approximately 10% of new drug approvals technically being prodrugs. We will set out to establish a synthetic and formulation strategy to produce a novel immunogenic prodrug platform, and upon subcutaneous metronomic dosing, we will evaluate the preclinical performance of our prodrugs as monotherapy and in combination with immunotherapy in breast and prostate cancer mouse models. We anticipate that exploiting the technological and socio-economic potential of PRIME will unlock new avenues towards at-home cancer treatment opportunities with enhanced therapeutic outcomes and improved patient quality-of-life.

Chronic kidney disease (CKD) affects 10% of the population and fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of CKD. Myofibroblasts are the key ECM producing cells and are activated by cross-talk with injured proximal tubule anChronic kidney disease (CKD) affects 10% of the population and fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of CKD. Myofibroblasts are the key ECM producing cells and are activated by cross-talk with injured proximal tubule and immune cells. Although a derangement in fatty acid oxidation (FAO) of tubular epithelium is crucial in the pathophysiology of CKD, the metabolic rewiring of kidney myofibroblasts remains elusive. Our preliminary observations suggest that cell type-specific metabolic shifts could define new cellular subpopulations with a differential role in the fibrogenic response. To understand this, the following objectives have been defined: 1. To decipher the role of FAO in myofibroblasts during kidney fibrosis; 2.To dissect metabolic changes as important drivers of kidney fibrosis and CKD; 3. To validate key metabolic pathways in complex ex vivo models of kidney fibrosis. To address these aims, I will map the genetic and metabolic spatio-temporal features of kidney fibrosis by a combination of cutting-edge multi-omics technologies at large scale (Spatial single cell ATAC sequencing for transcriptomics and Space M for metabolomics). This will be complemented by advanced computational analyses and modeling, using CKD human biopsies and mouse renal samples from available genetic models for myofibroblast tracing and FAO enhancement. Innovative in vitro systems (cell coculture and kidney organoid systems) will be used to identify and target cell type-specific metabolic reprogramming. Strategies based on the modulation of these metabolic shifts will provide a firm basis for novel, metabolism-oriented therapeutic approaches against renal fibrosis and CKD.