Researchers: Ling Tao, PhD and Eveline Bargieri, MD, PhD
Research project: Targeting Glutaminolysis to Overcome Neuroblastoma Resistance to mTOR Inhibition
Neuroblastoma (NB), similar to other solid tumors, grows in a harsh microenvironment with lack of oxygen and nutrients. However, tumors with high expression of a gene called MYCN (the primary driver of NB growth) survive, evade treatment, and eventually progress, resulting in less than 50% survival rate. How MYCN helps tumor survive and grow remains poorly understood.
Our research has shown that MYCN promotes the consumption of glutamine, a nutrient that is essential for NB cell survival and drug resistance. When we block a key enzyme in glutamine metabolism called glutaminase 1 (GLS1), using a clinically available drug (CB-839) has the potential to overcome the factors that drive NB growth.
We also know that another signaling pathway called mTORC1 promotes NB cell growth. Temsirolimus (TEM) is a drug that can inhibit mTORC1 signaling.
In this study, we are using a sophisticated tool known as “metabolomics” to assess how MYCN allows NB cells to grow. This data will subsequently be used to evaluate the anti-tumor activity of combinations of novel drugs in pre-clinical models of NB to see if we can restore the sensitivity of the tumor to the standard treatments that inhibit NB cell growth.
We have made substantial progress in completing the first Aim and over the next year, we will focus on evaluating these novel treatment approaches to assess if we can restore the sensitivity of NBs with high MYCN expression.
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