Investigating Smac mimetic compounds as a therapy against aggressive neuroblastoma


Identification: Michalicka, Matt


Description

Investigating Smac mimetic compounds as a therapy against aggressive neuroblastoma
 
Matthew Michalicka, Shawn Beug, Eric LaCasse and Robert Korneluk
University of Ottawa, Children's Hospital of Eastern Ontario Research Institute
 
Neuroblastoma is the third most common pediatric cancer, and despite aggressive therapeutic strategies, the five year survival rate for high-risk patients remains low. Dinutuximab is a recently approved monoclonal antibody targeting GD2, a ganglioside ubiquitously present on neuroblastoma, and its therapeutic use has improved high-risk patient outlook. Recent studies have shown that anti-GD2 therapy activates PD1-PDL1 signalling, resulting in the inhibition of its full therapeutic potential. The PD1-PDL1 signalling axis is a cellular checkpoint that inhibits immune responses, and blocking of this interaction has been successful in the treatment of numerous cancers. PD1 signalling has been investigated in neuroblastoma and a Phase 1 clinical trial of a PD1- and GD2-targeting combination therapy is underway. The Inhibitor of apoptosis proteins (IAPs) are commonly upregulated in cancers and prevent cell death through the inhibition of caspases. Smac mimetic (SM) compounds have been designed to prevent IAP-caspase interactions, thereby promoting cancer cell death. We discovered that SMs synergize with relevant neuroblastoma therapies, such as anti-GD2 or anti-PDL1, in a preclinical syngeneic, orthotopic mouse model. Antibody-dependent cellular cytotoxicity and modulation of the tumour microenvironment were found to be important contributors to the treatment efficacy. Overall, the combination of SMs with immunotherapies holds great promise for the treatment of neuroblastoma.
 
Funded by the CIHR, CCSRI and Ottawa Regional Cancer Foundation.

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