Embryonal Cancer Therapy and Prevention

Contact: Dr Belamy Cheung, bcheung@ccia.org.au

MYCN (N-myc) is a major oncoprotein that contributes to the progression of many paediatric and adult cancers. MYCN oncogene amplification and consequent N-Myc mRNA and protein over-expression are seen as a clonal feature in a quarter of tumours, and correlate with poorer prognosis in children with neuroblastoma. Deregulation is frequently associated with poor outcomes.

The ubiquitin-proteasomal mechanism has been characterised as controlling the levels and the activities of MYCN. Ubiquitin-specific proteases (USPs), such as USP28, USP36, and USP37, have been shown to stabilise and enhance c-MYC protein activity, and USP7 has been shown to deubiquitinate and stabilise N-MYC in neuroblastoma. Recently, we identified a number of small molecule drugs which enhance the anticancer activity of histone deacetylase inhibitors (HDACI). In combination with HDACIs these drugs inhibit cancer cell growth by targeting USP levels and MYCN protein for degradation, thus inhibiting tumour growth in TH-MYCN transgenic mice.

We hypothesise that USPs are specifically enhancing the stability and activity of MYCN oncogenesis. The overall aim of our study is to characterise the mechanisms by which USPs regulate the deubiquitination of MYCN, develop selective and potent inhibitors of USPs, and evaluate the efficacy of combination therapies for the treatment of MYCN-driven cancer.

Contact: Dr Belamy Cheung, bcheung@ccia.org.au

Neuroblastoma is an embryonal child cancer with heterogeneous phenotypes, ranging from tumours that spontaneously regress to those that are highly aggressive and incurable. Neuroblastoma arises due to defects in sympathetic neuron differentiation during foetal development. Our group uses genetically engineered mouse models to investigate the genesis of child cancer. In this project, we are examining the role of factors such as maternal diet in the prenatal initiation of embryonal child cancer.

Recent findings from our lab and those of our collaborators suggest that environmental factors such as high birth weight, certain maternal dietary supplements, and nitrous oxide exposure during neonatal age, are associated with an increased occurrence of childhood cancer. The molecular mechanisms behind these associations are unknown; thus, we are establishing in vitro and in vivo models to better understand these associations in relation to the initiation and development of childhood cancer.

This project is suitable for PhD/Honours students, and has the following aims:

• To evaluate impacts of dietary supplements, hormones and vitamins during pregnancy on initiation and development of neuroblastoma in mice offspring.
  
  
• To understand initiation and development of neuroblastoma in the presence/absence of different environmental factors, using cell lines and neurospheres.

Contact: Dr Belamy Cheung, bcheung@ccia.org.au

MYC is the most frequently amplified oncogene and is implicated in more than 70% of human malignancies. As it lacks a defined catalytic or regulatory site amenable to small molecule inhibition, there has yet to be an effective treatment for MYC-driven cancers, despite extensive research.

We are investigating indirect approaches to suppress MYC expression by targeting MYC regulatory proteins that are essential for its stability and oncogenic function. Previous research in our lab uncovered a novel MYCN binding protein, PA2G4, which stabilises MYCN and prevents it from targeted degradation, hence driving neuroblastoma tumorigenesis. Treatment of cells with a PA2G4 inhibitor called WS6 decreases both PA2G4 and MYCN expression in vivo and in vitro. WS6 is hypothesised to disrupt the PA2G4/MYCN interaction by binding to PA2G4. This decreases MYCN stability, enabling targeted degradation and reducing the malignant phenotype.

Translation of this research to a c-MYC-driven neuroblastoma model has shown promising preliminary results. High and low levels of c-MYC expression correlated with high and low PA2G4 expression levels, respectively. High PA2G4 levels were also associated with increased cell viability in neuroblastoma cells with high c-MYC. These results demonstrate a possible interaction between c-MYC and PA2G4. This study therefore aims to further investigate the interaction of c-MYC and PA2G4 in c-MYC-driven malignancies. Since c-MYC is implicated in more than 70% of human malignancies, this research will pave the way for better treatment of numerous human cancers.