Journal of Clinical & Experimental Pharmacology

Developing lead compounds that restore death sensitivity to trophic withdrawal in MYCN-initiated death resistant cells

8^th World Congress on Pharmacology and Toxicology

July 24-25, 2017 Melbourne, Australia

Belamy B Cheung, Owen Tan, Jessica Koach, Selina Sutton, Sonya M Diakiw, Carol G Au, Kacper Jankowski, Toby N Trahair, Shizhen Zhu, Daniel R Carter and Glenn M Marshall

UNSW Lowy Cancer Research Centre, Australia
Biochemistry and Molecular Biology Centre, USA
Kids Cancer Centre, Australia

Scientific Tracks Abstracts: Clin Exp Pharmacol

Abstract:

Embryonic cancer arises from postnatal persistent embryonal remnant or rest cells that are uniquely characterized by the absence of p53 mutations. We have showed that c-Myc and Myc N-overexpressing perinatal murine pre-B lymphocytes are resistant to apoptosis induced by interleukin-7 (IL-7) withdrawal and are associated with decreased p53 induction. From an initial library of 40,000 compounds, we generated a list of 56 hit compounds that displayed activity against Myc N-expressing pre-B cells in the absence of IL-7, but had minimal effect on cells in the presence of trophic factor. One of the lead compound, PB-798, reduced ganglia cell growth only in the absence of NGF and restored sensitivity to NGF withdrawal-induced cell death in myc N-expressing ganglia cells from TH-myc N homozygous mice, suggest that PB-798 can restore death sensitivity to trophic withdrawal in Myc-driven persistent rest cells. Furthermore, we investigated the potential mechanisms of cell death initiated by PB-798. By western blot, we found PB-798 treatment after 72 hours at 10 μM significantly reduced myc N protein levels in myc N-expressing clone F cells. We performed Affymetrix gene arrays and nanostring analysis to investigate the key genes/signaling pathways involved in the mechanism of cell death. We found that seven signaling pathways were significantly enriched. We have now identified 7 target genes in steroid biosynthesis and 5 target genes in JAK/STAT signaling pathways as the potential molecular targets for PB-798 drug action. Importantly, we have tested the efficacy of PB-798 in Myc N over-expression zebrafish neuroblastoma model and found that PB-798 significantly inhibits myc N-induced neuroblastic hyperplasia in the inter-renal gland (IRG) of this Myc N over-expression zebrafish model. PB-798 will be further tested in in vivo models of myc-driven tumor initiation such as the Eμ-Myc mouse model of lymphoma and the TH-myc N neuroblastoma mouse model.

Biography :

Belamy B Cheung was graduated from Sun Yat-sen University of Medical Science, Guangzhou, China and obtained her PhD degree at University of New South Wales, Australia. Presently, she is the Manager and Project Leader of the Molecular Carcinogenesis Program at Children's Cancer Institute Australia. Her research is currently focusing on drug discovery leading to the identification of small molecule inhibitors of oncogene targets. Most of her publications are in highly ranked journals, including Nature Reviews Cancer (IF37.9), Science Translational Medicine (IF15.8), Oncogene (IF 8.5) and Journal of the National Cancer Institute (IF14.3).

Email: BCheung@ccia.unsw.edu.au