John Silke-Projects

John Silke-Projects

Researcher: 
Professor John Silke

Projects

Last modified: 
Fri, 27/11/2015 - 1:34pm

The use of IAP antagonists to treat cancer

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.

References

  • Lalaoui N, Hänggi K, Brumatti G, Chau D, Nguyen NN, Vasilikos L, Spilgies LM, Heckmann DA, Ma C, Ghisi M, Salmon JM, Matthews GM, de Valle E, Moujalled DM, Menon MB, Spall SK, Glaser SP, Richmond J, Lock RB, Condon SM, Gugasyan R, Gaestel M, Guthridge M, Johnstone RW, Munoz L, Wei A, Ekert PG, Vaux DL, Wong WW & Silke J. Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell .2016; 29: 145-158. PMID: 26859455
  • Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, Richmond J, Ghisi M, Salmon JM, Silke N, Pomilio G, Glaser SP, de Valle E, Gugasyan R, Gurthridge MA, Condon SM, Johnstone RW, Lock R, Salvesen G, Wei A, Vaux DL, Ekert PG & Silke J. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med .2016; 8: 339ra69. PMID: 27194727

Team members

Dr Gabriela Brumatti, Dr Najoua Lalaoui

Can inhibition of necroptosis limit or reduce inflammatory diseases?

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.

References

  • Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RCJ, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, Silke J. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7 PMID: 25288762
  • Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA, Gerlic M, Silke J. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014 May 22;157(5):1175-88. PMID: 24813849

Team member

Dr Joanne Hildebrand

What role do IAPs and RIPK kinases play in generating an inflammatory response?

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.

Reference

  • Nachbur U, Stafford CA, Bankovacki A, Zhan Y, Lindqvist LM, Fiil BK, Khakham Y, Ko HJ, Sandow JJ, Falk H, Holien JK, Chau D, Hildebrand J, Vince JE, Sharp PP, Webb AI, Jackman KA, Mühlen S, Kennedy CL, Lowes KN, Murphy JM, Gyrd-Hansen M, Parker MW, Hartland EL, Lew AM, Huang DC, Lessene G & Silke J. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nat Commun .2015; 6: 6442. PMID: 25778803

Team member

Dr Ueli Nachbur

How does the master regulator of inflammation, TNF, perform its role?

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.

Reference

  • Feltham R, Webb AI, Silke J. SPATA2 - Keeping the TNF signal short and sweet. EMBO J .2016 PMID: 27470000