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Anti-antioxidant therapy?
08-09-2016
by Kelsey Kaustinen  |  Email the author
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COLD SPRING HARBOR, N.Y.—Though survival rates have improved for many cancers in the past decade, statistics still remain grim for some, among them pancreatic cancer. This cancer type has the worst survival rate of all major cancers, with little more than 5 percent of patients living five years after diagnosis.
 
The American Cancer Society forecasts that approximately 53,070 people will be diagnosed with pancreatic cancer in the United States this year, with an estimated 41,780 deaths in 2016 as a result of this cancer type. All told, pancreatic accounts for only 3 percent of all cancers in the United States, but roughly 7 percent of cancer deaths. It is the third leading cause of cancer-related deaths in the country, and is expected to become the second leading cause by 2020.
 
But recent research out of Cold Spring Harbor Laboratory (CSHL) is taking aim at this cancer with a new approach to targeting tumors: reducing their antioxidant levels. Prof. David Tuveson of CSHL, director of research for The Lustgarten Foundation, led this work.
 
Cancer cells produce more oxidants, but also generate more antioxidants as well, so shutting off the latter could lead the cells to self-destruct. Cancer therapies such as chemotherapy or ionizing radiation treatments work due to oxidation; if cells detect excessive oxidation, they trigger apoptosis.
 
In their efforts to find a way to decrease antioxidant levels in cancer cells, the research team focused on NRF2, which regulates redox homeostasis. When the protein is active, cells synthesize glutathione, an important antioxidant. NRF2 also supports pancreatic tumor maintenance and “promotes EGFR signaling to fuel cap-dependent mRNA translation,” as noted in the paper. While its role in synthesizing an antioxidant would make it seem like an ideal target in the effort to lower antioxidant levels, trying to knock out NRF2 is not without issues; as a transcription factor, the protein regulates the activity of numerous other genes.
 
The team used normal, pre-malignant and malignant pancreas organoids to illustrate what it would look like if NRF2 was completely eliminated. The pre-malignant organoids had cellular mutations in the kras gene, while the malignant organoids had a kras mutation and a mutation that inactivated p53, a tumor suppressor gene; these two mutations are found in most human malignancies.
 
When NRF2 is eliminated, protein synthesis becomes extremely sensitive to fluctuations in the balance between oxidants and antioxidants, but it is not impacted in normal pancreas cells—something known as synthetic lethality.
 
Chio noted that “This meant that if we could find a way of reducing antioxidants, protein synthesis would only be impacted in precancerous and malignant cells, a potentially powerful therapeutic strategy.”
 
As noted in the abstract of their paper, “NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.”
 
With this information in hand, the team moved on to mouse models with a combination of two drugs: an AKT inhibitor, which inhibits the beginning of the translation process for protein synthesis, and BSO, an agent that inhibits synthesis of glutathione.
 
“This is where our pancreas organoid system was so valuable,” noted Chio. “We were able to test this idea and see that this approach was synthetically lethal – it did increase the killing power of the AKT inhibitor, but the synergy was not present in the setting of normal pancreas cells.”
 
The two agents together had a synergistic effect in the mouse model, though the survival benefit was comparatively small—that, however, is something the team thinks they can improve by using different translation inhibitors and antioxidant synthesis repressors.
 
“Pancreatic cancer employs NRF2 as one of its henchmen to promote bad behavior, but the details were previously unclear. By developing organoid models, Christine, proteomics expert Darryl Pappin of CSHL and their collaborators pursued the basic biology of NRF2 to unravel the molecular underpinnings of this protein and thereby propose new therapeutic approaches for patients. We plan to translate Christine’s findings to early-phase clinical trials in the near future,” said Tuveson, who is director of The Lustgarten Foundation Pancreatic Cancer Research Laboratory and deputy director of the CSHL Cancer Center.
 
The findings were published in a paper titled “NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer,” which was posted online in Cell July 28.
 
Code: E08101604

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