DON and small molecule Bcl-2 family antagonists treating glutamine addicted cell lines for Neuroblastomas and Ewing sarcomas (SJ-13-0026)

St. Jude Reference #SJ-13-0026

Description

MYC oncogenes are associated with the majority of adult cancers as well as aggressive pediatric cancers such as medulloblastoma, neuroblastoma (NBL) and Ewing’s sarcoma (EWS). There is growing interest in targeting the consequences of Myc oncogenes including aberrant metabolism since directly blocking Myc transcription factors has not worked in the past. This is an approach researchers at St. Jude Children’s Research Hospital have explored in NBL and EWS. In multiple types of cancer, high-level MYC expression drives an addiction to glutamine that does not exist in normal cells. This addiction comes from glutamine’s unique role in replenishing metabolic pathways depleted in generating biomaterial for rapid cell growth. Researchers at St. Jude hypothesized that MYC-driven Ewing’s Sarcoma and MYCN amplified neuroblastoma would be sensitive to DON (6-diazo-5-oxo-l-norleucine) an inhibitor of glutamine metabolism. DON has previously been used in pediatric clinical trials, but was never extensively clinically tested in MYC-driven malignancies.

The investigators also reasoned that the death signal from loss of glutamine metabolism would be partially blocked by BCL-2 family members and that BCL-2 inhibitors might augment the effects of DON. This has led to the discovery that DON can be combined with BCL-2 antagonists, like navitoclax (ABT-263) to treat a large subset of cancers.  In vitro, this combination caused an increase in DON activity across the entire panel of cell lines tested, with synergistic effects in two of the N-MYC amplified neuroblastoma cell lines. The corresponding publication supports targeting glutamine metabolism to treat MYC overexpressing cancers, such as NBL and EWS, particularly in combination with Bcl-2 family antagonists.

Scientific references below include a Cell Biochemistry and Function paper that confirms this work, and a publication showing that DON is effective in medulloblastoma in addition to neuroblastoma. An external author in both of the abstracts and a pediatric oncologist at John Hopkins is interested in starting clinical trials with DON in pediatric patients. The idea of combining glutamine inhibitors with inhibitors of Bcl-2 family members appears to be a promising treatment idea.


 

Keywords

DON, MYC, cancer, Bcl-2, apoptosis, glutamine addicted, glutamine inhibitor


 

Granted Patents or Published Applications

International PCT patent application published May 2, 2013 as WO 2014/160071


 

Related Scientific References

Olsen RR, Mary-Sinclair MN, Yin Z, Freeman KW. Antagonizing Bcl-2 Family Members Sensitizes Neuroblastoma and Ewing’s Sarcoma to an Inhibitor of Glutamine Metabolism. PLoS ONE 10(1):e0116998, 2015. doi:10.1371/journal.pone.0116998

Harnett CC, Abusneina A, Clément J, Gauthier ER, Inhibition of MCL-1 by obatoclax sensitizes Sp2/0-Ag14 hybridoma cells to glutamine deprivation-induced apoptosis. Cell Biochem Funct. 2015 Jul;33(5):334-40. doi: 10.1002/cbf.3121. Epub 2015 Jul 15.


 

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