Targeting metastasis with chemo and immunotherapy
The large majority cancer-related deaths are caused by metastases that do not respond or have acquired resistance to available therapies. Acquisition of a mesenchymal phenotype by epithelial cancer cells has emerged as a key mechanism that confers a pro-invasive behaviour and resistance to anti-cancer treatments, including chemo- and immunotherapy. Transforming growth factor-β (TGF-β) is a main driver of epithelial to mesenchymal transition (EMT) and targeting TGF-β inhibits the formation of metastases and limits resistance against anti-cancer agents. However, TGF-β also plays an important role in maintaining tissue homeostasis, thereby making it a challenging target for cancer therapy. Indeed, while showing anti-cancer benefit in human patients, current TGF-β targeting agents exhibit unwanted side-effects, and thus fail to advance beyond phase 2 clinical trial testing. We are employing multiple strategies to specifically target TGF-β-induced EMT of cancer cells. For example, we repurpose existing drugs to selectively change the behaviour of aggressive mesenchymal cancer cells into non-invasive and therapy sensitive cancer cells or benign terminally differentiated cells. In addition, we performed CRISPR-Cas9 library genetic screens to find pivotal modulators to induce MET or increase efficiency of cytotoxic T cell killing of mesenchymal cancer cells.
TARGETING TGF-b BY REDIRECTING SIGNALING ENGINEERING
TGF-β is a highly multifunctional cytokine with context dependent effects on many different cell types. Using genetic, proteomic, glycomic and small molecule screens we have identified numerous targets and mechanisms to inhibit, activate or redirect TGF-β receptor signalling. For example E3 ubiquitin ligases and deubiquitinating enzymes were identified that control the stability of TGF-β receptors or inhibitory SMAD proteins. Small molecule enzymatic inhibitors have been developed to mitigate the overactive TGF-β signalling in aggressive cancer cells. Moreover, we are elucidating the mechanisms by which parasite-derived TGF-β mimics (with sequence and structure distinct from TGF-β) suppresses the host immune response. We anticipate that the in-depth understanding of their mechanism of action will allow for the development of novel TGF-β agonists or antagonists in a cell type specific manner.
ENGINEERING NOVEL BIOMOLULE DEGRADERS FOR THERAPEUTIC GAIN
PROTACs are bifunctional molecules that recruit an E3 Ubiquitin ligase to target protein for proteasomal degradation. We are developing novel PROTAC approaches to target intracellular signalling molecules for degradation. In addition, we are advancing LyTACs to target pro-oncogenic membrane receptors for lysosomal degradation, and RIBOTACs to target tumor promoting lncRNAs for ribonuclease-mediated degradation.
