Silke Lab

We are taking several approaches to explore the best way that IAP antagonists can be used in the clinic to treat cancer. This is an area of intense research world-wide but we have unique advantages including:
* Access to amazing patient-derived xenograft resources.
* A longstanding collaboration with TetraLogic Pharamceuticals Corporation which is developing birinapant, an IAP-antagonist, in clinical trials.
* The institute’s high throughput screening facility.

Using these reagents we are looking for the cancer types most responsive to birinapant killing and novel drug combinations that can overcome the resistance of other cancer types.

Using laboratory models of psoriasis and systemic inflammation we have shown that genetic loss of the key necroptosis effectors RIPK3 and MLKL significantly attenuates many aspects of the disease.

Working with other divisions at the institute, we have discovered novel small molecular inhibitors of necroptosis which we are now testing in this and other disease models.

We have shown that IAPs and RIPK2 play an important role in regulating signalling from NOD receptors, essential intracellular receptors that detect and respond to bacterial products. We are exploring a small molecule approach to explore this pathway and with collaborators at the institute we have developed and characterised a new RIPK2 inhibitor.

This has a fascinating mode of action: it delays signalling events such as NF-κB activation by only an hour or less, but completely inhibits the production of inflammatory cytokines by this pathway. We are exploring this further with mass spectrometry approaches.

cIAPs and RIPK1 play important roles in regulating the signalling outcome downstream of TNF/TNFR1 activation. We have a long-standing interest in understanding how they function in this role, using a combination of genetics, small molecule inhibitor and mass spectrometry approaches.

More recently we have expanded our purview of this fascinating signalling paradigm by exploring the role of other regulators of this pathway including the linear ubiquitin assembly complex comprising the proteins SHARPIN, HOIL-1 and HOIP.