Oral Presentation Advances in Neuroblastoma Research Congress 2016

Targeting a novel MYCN onco-factor, PA2G4, for the treatment of neuroblastoma (#20)

Jessica Koach 1 , Jayne E Murray 1 , Joshua McCarroll 1 , Giorgio Milazzo 2 , Giovanni Perini 2 , Michelle Haber 1 , Murray D Norris 1 , Jamie I Fletcher 1 , Belamy B Cheung 1 , Glenn M Marshall 3
  1. Children's Cancer Institute Australia, Randwick, NSW, Australia
  2. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
  3. Kids Cancer Centre, Sydney Children’s Hospital, Sydney, NSW, Australia

MYCN oncogene amplification is found in one third of primary neuroblastoma at diagnosis, and correlates with poor prognosis. We have defined increased MYCN protein stability as a necessary feature during MYCN-related tumorigenesis, providing a completely novel therapeutic target (1-2).

For the first time, we have identified Proliferation-Associated protein 2G4 (PA2G4) as a direct protein-binding partner of MYCN which acts in a forward feedback expression loop with MYCN to drive neuroblastoma tumourigenesis. PA2G4 belongs to a family of DNA/RNA binding proteins already implicated in cell growth, apoptosis and differentiation. High PA2G4 expression correlated with high expression of MYCN in neuroblastoma cells and tumour tissues, and, strongly predicted poor neuroblastoma patient survival. Suppression of PA2G4 by siRNAs decreases neuroblastoma cell growth, cell migration and colony formation. Most significantly, our in vivo data showed stable overexpression of PA2G4 in a non-tumorigenic neuroblastoma cell line was able to induce tumour growth. Conversely, using nanoparticles to deliver siRNA targeting PA2G4, we were able to delay neuroblastoma tumour growth significantly in a mouse xenograft model. Furthermore, a small molecule known to bind PA2G4, WS6, significantly decreased PA2G4 levels in tumour tissues and tumorigenicity in TH-MYCN mice.

Collectively, our data suggest that PA2G4 acts as an onco-factor, binding and protecting MYCN from proteolysis, thus increasing MYCN levels. Our research provides strong evidence demonstrating PA2G4 is a driver of tumorigenicity and for the first time identifies PA2G4 as a novel therapeutic target for the treatment of neuroblastoma.

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