A drug used to target IDH1 mutations in select cancers also appears to inhibit the wild-type form of the enzyme, under certain conditions. This feature explains why a large group of different cancers are vulnerable to the drug. This discovery opens up the possibility that the drug, Ivosidenib or AG-120, could become more broadly applicable against a variety of cancers, given that mutant IDH1 is present in just 1% of cancers. The findings were recently published in Nature Cancer.
“Historically, only a few groups have cared about wild-type IDH1,” said Jordan Winter, MD, Division Chief of Surgical Oncology at University Hospitals (UH) Seidman Cancer Center and senior author on the study. Dr. Winter is also John and Peggy Garson Family Endowed Chair in Pancreatic Cancer Research and Jerome A. and Joy Weinberger Family Master Clinician in Surgical Oncology. “IDH1 therapeutic investigations have principally focused on the development of mutant IDH1 inhibitors. Less than a handful of reports have focused on wild-type IDH1 inhibition. We showed, along with a few others, that wild-type IDH1 is an important target. We think that Ivosidenib, previously called AG-120, may be applicable to the large majority of cancers-the one percent with mutant IDH1 and the remaining 99% with wild-type IDH1.”
Fundamental to this discovery is the observation that cancer cells rely on IDH1 metabolism to thrive in a harsh and nutrient-deprived tumor microenvironment. Nutrient limitation universally present in pancreatic tumors could open a new therapeutic window, explains the study’s first author Ali Vaziri-Gohar, PhD, Postdoctoral Fellow in the Department of Surgery at Case Western Reserve University School of Medicine.
“Wild-type IDH1 activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu,” he said. “We found that IDH1 is very important for cancer cells’ survival in a stressful microenvironment. When the cancer cells have less oxygen and less glucose or glutamine, anything that hurts them, they need a defense mechanism to protect them, which is this important molecule IDH1.”
In laboratory experiments, Dr. Winter, Dr. Vaziri-Gohar, and colleagues demonstrated that genetically suppressing IDH1 reduced growth of pancreatic cancer cells in cell culture under low nutrient conditions and in mouse models of pancreatic cancer. They found, too, that the FDA-approved inhibitor of mutant IDH1, Ivosidenib, was surprisingly potent against the wild-type form of the protein-especially when paired with the important condition of low magnesium. This latter point had been overlooked in prior studies.
Dr. Vaziri-Gohar said that this finding was a bit of scientific serendipity.
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