Pharmacology and Toxicology

Biography

Biography: Belamy B Cheung

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.