Northwestern Medicine scientists have developed a promising approach to killing treatment-resistant cancer cells by exploiting their hidden metabolic vulnerabilities, according to a study published in the Proceedings of the National Academy of Sciences (PNAS).
Ferroptosis — a type of programmed cell death — occurs when the accumulation of iron triggers excessive oxidation of fats in cell membranes, ultimately causing the cell to break down. Cancer cells that resist conventional treatments often rely on antioxidant defenses to survive, and disrupting these defenses could be key to new therapies, said Shad Thaxton, ‘04 MD, ‘07 PhD, ’06 ’08 GME, associate professor of Urology and senior author of the study.
“Previously, we showed that a drug that we are developing to treat cancer, a synthetic lipoprotein particle, was highly effective at killing cancer cells by a mechanism consistent with ferroptosis,” said Thaxton, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “In this work, we utilized a powerful genetic screening tool to better understand how our drug is working to kill cancer cells.”
One critical antioxidant enzyme in cancer cells, called glutathione peroxidase 4 (GPx4), prevents the lipid oxidation that breaks down the cancer cell membrane and blocks ferroptosis. By targeting the cancer cell receptor SR-B1 with the synthetic lipoprotein particle they developed, Thaxton and his collaborators found they could strip cancer cells of GPx4, making them vulnerable to lipid oxidation and, ultimately, ferroptosis.
In the current study, investigators in the Thaxton laboratory ran a genetic screen on ovarian cancer cells. They found that two genes — ACSL4 and TXNRD1 — were key players involved in how the drug worked to kill the ovarian cancer cells. ACSL4 was necessary for ferroptosis, while TXNRD1 led the investigators to selenium, an element essential for GPx4.
“These experiments extend and enhance our original observations in lymphoma by identifying a metabolic target, GPx4, that isn’t tissue agnostic but rather linked by sensitivity to ferroptosis and therefore applicable to a wider range of malignancies , including ovarian and renal cancers,” said Leo I. Gordon, MD, the Abby and John Friend Professor of Oncology Research and professor of Medicine in the Division of Hematology and Oncology, who was a co-author of the study.
“This study provides new and valuable information on the processes governing sensitivity to ferroptosis and ferroptosis-inducing therapies by focusing on the role of ASCL4 and lipid remodeling. This is a significant shift in focus that so far has emphasized iron and mechanisms that regulate labile iron availability,” said Marcelo Bonini, PhD, professor of Medicine in the Division of Hematology and Oncology, also a co-author of the publication.
This is the first time scientists have identified specific metabolic targets that can be manipulated to kill cancer cells using a single, multifunctional drug. The findings illustrate how targeting cancer metabolism can lead to innovative treatment strategies for hard-to-treat cancers, Thaxton said.
“Individuals often exhaust available treatment options and at some point get the news that the cancer has come back,” Thaxton said. “Ours and others’ data suggest that this therapeutic approach may provide new opportunities to treat these types of cancers that increase mechanisms to reduce oxidation and become resistant to traditional cancer therapy.”
Now, Thaxton and his laboratory will work toward testing the treatment in patients, he said.
“We hope to deliver our therapy to treat patients suffering from cancer,” he said. “By understanding the mechanism through which the drug works, we are also now actively exploring other new therapies that may one day become part of the arsenal of treatments for cancer.”
Sophia Lamperis, a PhD student in the Driskill Graduate Program in Life Sciences (DGP), was the first author of the study. Additional Feinberg co-authors included Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care; and Daniela Matei, MD, the Diana, Princess of Wales Professor of Cancer Research and chief of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology. Chandel, Matei and Gordon are members of the Lurie Cancer Center.
The study was funded by a V Foundation grant, a T32 Physical Genomics Training Fellowship and the Dr. John N. Nicholson Fellowship at Northwestern University. Additional funding was provided by an H Foundation Postdoctoral Award from the Lurie Cancer Center.
