Almost half of children with high-risk neuroblastoma harbor extra copies of the gene MYCN (MYCN amplified), the primary driver of neuroblastoma and its resistance to therapy. However, no available therapies directly target MYCN. In a paper published in Nature Communications, researchers from Baylor College of Medicine delved into understanding metabolic vulnerabilities of MYCN-amplified neuroblastoma to see if they could pinpoint strategies for exploiting MYCN’s role and lead to new treatments.
The teams learned that MYCN amplification rewires a tumor’s lipid metabolism such that it promotes the use and biosynthesis of fatty acids to grow. “We found that MYCN is driving the dependency on lipid metabolism in neuroblastoma,” said senior author Eveline Barbieri, MD, PhD. “Cells with extra copies of MYCN depend highly on fatty acids for their survival; lipid metabolism is a key metabolic pathway for MCYN-driven neuroblastoma tumors.” The findings were confirmed in both MYCN-amplified cell lines and in MYCN-amplified patient tumor samples.
The team used an unbiased, metabolomics analysis of primary patient tumor samples comparing the metabolic profiles of MYCN-amplified neuroblastomas to the profiles of non MYCN-amplified neuroblastomas. The results showed important differences between tumor cell utilization of specific nutrients for tumor growth in these two tumor groups, including lipid, amino acid, carbohydrate, and nucleotide pathways—with lipid metabolism as the most significant. Barbieri and her colleagues hypothesized that MYCN reroutes lipid metabolism so that fatty acids are readily available to cancer cells, thereby promoting tumor cell growth.
In this analysis, the researchers learned that MYCN binds and activates the fatty acid transport protein (FATP2), a molecule that mediates cellular uptake of fatty acids. “This was a novel discovery, that MYCN was driving the expression of FATP2 and uptake of fatty acids,” added Barbieri. “The increase in fatty acid update contributes to neuroblastoma oncogenesis.” FATP2 has also been described in other cancers, such as melanoma.
When the researchers applied a FATP2 small-molecule inhibitor, they saw reduced tumor growth of MYCN-amplified neuroblastoma tumors in mice models. In in vitro tests, this inhibition of fatty acid uptake did not affect normal cells or tumors lacking MYCN-amplification. “We think this is a selective vulnerability in MYCN-amplified tumors cells,” said Barbieri.
By reprogramming tumor metabolism, specifically lipid metabolism, the researchers sensitized tumors to conventional chemotherapy. “I do not think this strategy can be used as a single therapy—inhibiting fatty acid uptake will not be sufficient as a single agent,” said Barbieri, “but the fact that it potentiates the effect of chemotherapy is an important aspect because in mice the combination of the two is particularly effective in blocking tumor growth.”
There are other MYCN-amplified pediatric cancers, including in some pediatric rhabdomyosarcoma, medulloblastoma, Wilms tumor, and retinoblastoma. In adults, MYCN-amplified tumors are found in some prostate cancers, small-cell lung cancers, and basal cell carcinomas. Research has shown that amplification of MYCN in most of these adult cancers is associated with a poor prognosis.
“New strategies for disrupting MYCN oncogenic programming are critical for developing effective neuroblastoma therapies and potentially for other MYCN-amplified cancers,” Barbieri said. “Inhibiting fatty acid update is likely to be an effective approach for improving current treatment regimens.”
