Targeting MYC and Metabolism in Childhood Neuroblastoma for Precision Medicine

Childhood neuroblastoma develops in the peripherical nervous system.

Building on our previous work we will  i) explore the antioxidant enzyme PRDX6 as target for tailored medicine for NB; ii) analyze the potential of OMOMYC, the first in-man medicine against MYC in clinical trials, for effects on NB cells and tumors in mice; iii) employ the druggable conformational switch, coreMYC, which we recently identified in the c-MYC transactivation domain, as “bait” for library screening of small molecules/drugs inhibiting MYC function; iv) develop a novel NB model enabling studies of NB initiation by using human induced pluripotent stem cells (hiPSCs) carrying a wild type or mutant form of PHOX2B present in familiar NB.

Together, this work will give insights into the potential of PRDX6 inhibitors alone and in combination with other antioxidant inhibitors as well as the potential of OMOMYC as strategies to target NB.

Importantly, we will utilize our recently identified on/off switch region in MYC to discover novel MYC inhibitors which will induce and keep the protein in an inactive state.

In addition, the new NB mouse model as well as the hiPSC organoids will provide new toolboxes both for analyses as well as identification of novel cancer treatments.

Our approach integrates organoid modeling, biophysical studies, library screenings, animal experiment, and drug discovery, holding promise for advancing our understanding of NB pathogenesis and identifying novel therapeutic strategies.