Researchers identify an Achilles' heel in neuroblastoma

"Treating neuroblastoma by directly targetingMYCNhas been challenging," said Dr. Eveline Barbieri, corresponding author of a recent study published in the journalNature Communications和儿科助理教授——hematology and oncology at Baylor College of Medicine and Texas Children's Hospital. "In this study we investigated new strategies to improve the survival of children withMYCN通过研究代谢放大神经母细胞瘤vulnerabilities that we could exploit to overturn these tumors' resistance to therapy."

Barbieri and her colleagues used an unbiased, metabolomics analysis to compare the metabolic profiles ofMYCN-amplified neuroblastomas to the profiles of nonMYCN-amplified neuroblastomas. The results of their innovative approach showed that there were important differences between tumor cell utilization of specific nutrients for tumor growth in these two tumor groups.

"We found thatMYCNamplification rewires a tumor's lipid metabolism in a way that promotes the use and biosynthesis of fatty acids, a type of lipid cells can use as a source of energy," Barbieri said. "Cells with extra copies ofMYCNdepend highly on fatty acids for their survival. We confirmed this both inMYCN-amplified cell lines and inMYCN-amplified patient tumor samples."

Barbieri and her colleagues hypothesized thatMYCNreroutes lipid metabolism so that fatty acids are readily available to cancer cells, thereby promoting tumor cell growth.

Looking into the mechanism

"When we investigated what promptedMYCN-amplified neuroblastomas to rely on fatty acids to grow, we discovered thatMYCNdirectly upregulates or enhances the production of fatty acid transport protein 2 (FATP2), a molecule that mediates cellular uptake of fatty acids," Barbieri said. "We then asked, what would happen if we interfered with FATP2 function inMYCN-amplified neuroblastomas?"

When the researchers neutralized FATP2 activity, either by knocking down the gene or by blocking FATP2 action with a small-molecule inhibitor, they reduced the growth ofMYCN-amplified tumors.

"We observed that when we blocked the import of fatty acids into the cancer cells, and there was a reduction in tumor cell growth," Barbieri said. "The interesting part is that inhibiting or blocking FATP2 had no effect on normal cells or tumors withoutMYCN-amplification. This seems to be a selective metabolic vulnerability ofMYCN-amplified tumors. They uniquely use this transporter to feed on fatty acids to grow."

There are otherMYCN-amplified pediatric and adult tumors.

"This approach may be applicable to many human cancers that utilize MYC for oncogenesis (about 50% of cancers overall) and provide new insight into the regulation of energy metabolism in cancer progression," Barbieri said.

These finding suggest that therapeutic interventions that interfere with FATP2 activity can potentially selectively block fatty acid uptake inMYCN-amplified tumors, stopping or reducing tumor growth and making them more sensitive to conventional chemotherapy.

"More work is needed before this approach can be employed in the clinical setting," Barbieri said. "But this study suggests that strategies to interfere with a tumor's nutritional dependence on fatty acids is a promising therapeutic strategy worthy of further investigation."

Other contributors to this work include first author Ling Tao and Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H. Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini and Cristian Coarfa. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, National Research Center-Cairo, University of Bologna, Texas Children's Hospital and Houston Methodist Hospital.

This study was supported by the Kate Amato Foundation and the Department of Defense (W81XWH-19-1-0556). See the publication for a full list of funding for each study author.