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Potential New Target for Treating Chemotherapy-Associated Kidney Damage

Dr. Zhao and his team found that inhibiting the APE2 protein in a preclinical model of cisplatin-induced acute kidney injury significantly helped attenuate disease pathology.

12/31/2020

Lerner Research Institute scientists have identified a novel target with potential utility for treating or preventing an unfortunate but common side effect of chemotherapy, according to new study findings published in Cancer Research.

The research team—led by Jianjun Zhao, MD, PhD, assistant staff in the Department of Cancer Biology and co-senior author Jianhong Lin, PhD, Case Western Reserve University—showed that targeting the protein APE2 (apurinic/apyrimidinic endonuclease 2) may help to prevent acute kidney injury in cancer patients treated with the chemotherapy drug cisplatin.

Unintended side effects of the “one-size-fits-all” treatment approach

Cisplatin is a standard-of-care chemotherapy drug used to treat a variety of cancers. While effective, it is administered using a one-size-fits-all approach. In some patients, the universal dose can cause unintended kidney damage that necessitates discontinuing treatment or reducing the dose, which may, in turn, compromise its cancer-fighting effectiveness.

Cisplatin works by damaging the genetic material in rapidly dividing tumor cells, interrupting DNA replication and preventing the spread of cancer cells. Dr. Zhao explained that cisplatin’s damage to non-cancer cells can occur, in part, while the body works to metabolize and excrete the drug.

“While the body excretes most of the administered cisplatin after about a day or so—as much as 50-80 percent of it—some does remain in the kidney,” said Dr. Zhao. “We see that specific cells in the nephron—the part of the kidney that removes waste and excess ‘stuff’ from the blood before it gets converted to urine—exhibit damage.”

Cisplatin increases APE2 expression, drives mitochondrial damage

Dr. Zhao and his team observed that preclinical models treated with cisplatin had increased levels of APE2 in the nephron cells, specifically called proximal tubule cells, and that it binds with another protein called MYH9 (myosin heavy-chain 9).

“We discovered that following cisplatin treatment, APE2 levels become elevated in a specific part of the proximal tubule cells, called the mitochondria. While less than what can be found in the chromosomes, mitochondria do contain a small amount of their own DNA,” said Dr. Zhao. “We believe that this abnormal APE2-MYH9 binding can compromise mitochondrial function and cause cells to die, resulting in the kidney damage commonly associated with cisplatin treatment.”

They found that genetically knocking out APE2 in preclinical models treated with cisplatin significantly reduced cisplatin-induced acute kidney injury, suggesting that pharmacologically targeting the protein may be a viable approach to treating the condition in humans.

Next steps

More research will be necessary, but Dr. Zhao says he’s very optimistic about their findings and looks forward to continuing the line of investigation.

“We can improve outcomes for cancer patients either by developing new therapeutics entirely or finding ways to optimize the ones we currently have. We are hopeful that our research will one day help to treat or prevent this chemotherapy side effect, which sometimes unfortunately requires physicians to alter a patient’s treatment regimen in a way that may compromise cisplatin’s cancer-fighting potency.”

Yi Hu, PhD, a postdoctoral fellow in Dr. Zhao’s lab, was first author on the study, which was supported in part by the National Institutes of Health.



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