Researchers Discover a Key Weak Spot in a Deadly Childhood Cancer



Neuroblastoma, a childhood cancer that develops from neural cells on the adrenal glands, kills 15% of children who die from cancer. The MYCN (MYCN amplified) gene, which is the primary cause of neuroblastoma and the main factor contributing to its resistance to therapy, is present in over 50% of children with high-risk neuroblastoma.

It has proven difficult to treat neuroblastoma by specifically targeting MYCN, according to Dr. Eveline Barbieri, an assistant professor of pediatrics - hematology and oncology at Baylor College of Medicine and Texas Children's Hospital and the study's corresponding author. In this work, we looked for metabolic vulnerabilities that we could exploit to overcome the resistance of these tumors to therapy. The goal was to improve the survival of children with MYCN amplified neuroblastoma.

Using an unbiased, metabolomics approach, Barbieri and her colleagues compared the metabolic profiles of MYCN-amplified neuroblastomas to the profiles of non-MYCN-amplified neuroblastomas. The way the two tumor groups utilised certain nutrients to fuel tumor growth was significantly different, according to their innovative methodology.

"We discovered that MYCN amplification rewires a tumor's lipid metabolism in a way that favors the usage and manufacture of fatty acids," Barbieri stated. "Fatty acids have a critical role in the survival of cells containing additional copies of the MYCN gene. Both MYCN-amplified cell lines and MYCN-amplified patient tumor samples allowed us to confirm this.

According to Barbieri and her coworkers, MYCN reroutes lipid metabolism so that cancer cells can easily access fatty acids, promoting the development of tumor cells.

We found that MYCN directly upregulates or improves the production of fatty acid transport protein 2 (FATP2), a molecule that facilitates cellular uptake of fatty acids, when we looked into what caused MYCN-amplified neuroblastomas to depend on fatty acids for growth, said Barbieri. Then, we wondered what would happen if we prevented MYCN-amplified neuroblastomas from functioning properly with FATP2.

The development of MYCN-amplified tumors was inhibited when the researchers neutralized FATP2 activity, either by knocking down the gene or by obstructing FATP2 action with a small molecule inhibitor.

According to Barbieri, "we found that there was a reduction in tumor cell development when we prevented the import of fatty acids into the cancer cells." The intriguing part is that normal cells or tumors lacking MYCN-amplification were unaffected by inhibiting or blocking FATP2. MYCN-amplified tumors appear to be particularly vulnerable to this metabolic weakness. They have a special transporter that they employ to consume fatty acids and develop.                                
Approximately 50% of all malignancies need MYC for oncogenesis, therefore this method may be applicable to many human cancers and shed fresh light on how energy metabolism is regulated as cancer progresses, according to Barbieri.          
These findings imply that therapeutic approaches that inhibit FATP2 activity may preferentially restrict fatty acid uptake in MYCN-amplified tumors, halting or slowing tumor growth, and increasing sensitivity to standard chemotherapy.

Before using this strategy in a therapeutic context, further work must be done, according to Barbieri. "However, our data implies that approaches to disrupt a tumor's need on fatty acids for sustenance is a viable therapeutic method deserving of additional consideration."

By BAYLOR COLLEGE OF MEDICINE 

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