Ubiquitin control of signaling
We have performed functional genetic screens to identify new key (druggable) components of TGF-b (and other) signaling pathways (signal transduction expansion project). Many of these regulators control the stability and/or activation of TGF-b transmembrane receptors or SMAD intracellular effectors. Some of these components like the ubiquitin specific proteases USP4 and 15 and the E3 ubiquitin ligase TRAF4 are highly expressed (and amplified at the gene level) in particular cancers. We are now developing small molecule drugs that target these protein activities in cancer and cardiovascular diseases in collaboration with others.
Restoring cellular homeostasis
An ongoing effort is the development of unique therapeutics by engineering synthetic bioactive molecules that inhibit or promote selective protein-protein interactions involved in TGF-b signaling, with the aim of inhibiting pathological responses in cancer or to stimulate intrinsic repair and regeneration in cardiovascular and bone/cartilage diseases. Examples of such molecules include macrocyclic peptides, nanobodies, PROTACs (Proteolysis targeting chimeric molecules) and macrocyclic kinase inhibitors.
Epithelial to mesenchymal transition
EMT is a latent developmental process, which is re-activated during cancer progression. Cancer cell Invasion, metastasis and chemoresistance are linked to EMT. We want to identify new druggable targets that interfere with this process. TGF-b is a main driver of EMT, which involves transcriptional reprogramming driven by specific EMT transcription factors, such as SNAIL, SLUG and ZEB1. In addition, we investigate signaling and genetic networks such as BMPs and OVAL1/2 transcription factors that play a key role in maintaining epithelial integrity, and may induce MET. Using genomic, proteomic and metabolic approaches we want to identify genes/proteins, post-translational modifications or metabolites whose activity/abundance/change plays a crucial role in the in the spatio-temporal control of EMT and the reciprocal process, MET.
Modulating immune responses
TGF-β also plays important roles in regulating stromal cells in the tumor microenvironment. TGF-β has potent immunosuppressive effects on both innate and adaptive immune cells, including dendritic cells, macrophages, natural killer cells, and CD4+ and CD8+ T cells. Moreover, TGF-β stimulates the differentiation of immune-suppressive regulatory T (Treg)-cells. i\Immune checkpoint inhibitors are showing promise in clinical trials and have been approved by the FDA. However, not all patients are responsive to these treatments, which may be due to overproduction of immunosuppressive TGF-b. Indeed, we have shown, in colon cancer models that a combination therapy consisting of immune checkpoint inhibitors and TGF-b targeting agents is a significantly more effective anti-tumor treatment compared to the single treatments alone.
Targeting cancer associated fibroblasts
Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the microenvironment of many types of tumors. CAFs can produce high amounts of TGF-b which plays a critical role in their activation, and promote invasive properties of cancer cells. Moreover, TGF-b-activated CAFs have been shown to promote immune evasion, protect tumors from conventional chemotherapy and provide metabolic support to tumors. We investigate these processes in pancreatic cancer patient derived organoid co-cultures with pancreatic stellate cells, aiming to develop specific therapeutic strategies to inhibit pathological TGF-b activity in CAFs.
Angiogenesis is a hallmark of cancer and a validated therapeutic target in the clinic. Despite their early promise, anti-angiogenic compounds which inhibit the VEGF pathway offer only limited survival benefits to patients principally because of the acquisition of resistance due to activation of alternative pathways. Thus, finding and validating new targets is a major challenge to the cancer field. Activin receptor-like kinase (ALK)1 and endoglin are TGF-β receptors predominantly expressed in actively proliferating endothelial cells (ECs). The ALK1/Endoglin signaling axis has been shown to play a pivotal role in regulating angiogenesis. We have developed nanobodies that specifically bind to ALK1 or endoglin, and small molecule macrocyclic molecules that inhibit ALK1 kinase activity. Our aim is to develop these as novel anti-angiogenic therapeutic agents, alone or in combination with other therapies.