An approved cancer therapeutic, once used in only 1 percent of cancers, may have significant uses in the remaining 99 percent, according to a new study.
“Ivosidenib, previously called AG-120, may be applicable to the large majority of cancers,” said senior author Dr. Jordan Winter, division chief of surgical oncology at University Hospitals Seidman Cancer Center in Cleveland.
Winter said that the therapeutic was previously used in the “1 percent” of cancers that carried a mutation, or change, in the IDH1 gene. However, scientists now believe it can also be used in the “remaining 99 percent” in cancer cells that carry the wild-type, or normal, IDH1 gene, under conditions that the environment is low in magnesium.
The IDH1 gene is very critical for cancer cells living in a harsh and nutrient-deprived environment.
“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,” said Dr. Ali Vaziri-Gohar, the lead author of the study, which was published on June 9.
In nutrient-deprived environments, IDH1 will activate, producing proteins that will neutralize the reactive oxygen species that are produced in this specific environment. If the reactive species are not neutralized, they will cause damage to cells, resulting in the stunting of growth of cancer cells and their death.
Ivosidenib, which has been approved by the Food and Drug Administration (FDA), was previously used to inhibit the mutated version of IDH1 in pancreatic cancer, so that cancers will be sensitized and die.
However, now that the researchers have identified its potency against wild-type IDH1 cancers, they have hopes that the therapeutic may be used against a wider range of cancers.
Some IDH1 cancers are acute myeloid leukemia, a cancer of the immune cells that is already being treated by this therapeutic, as well as brain cancer, though there are many others.
However, the study into Ivosidenib in cancer cultures has shown that it is at its most potent only under low magnesium concentrations, as magnesium prevents inhibition of IDH1.
Therefore, only under low magnesium concentrations can the drug inhibit IDH1, causing damage to the cells that are reliant on IDH1 to protect them.
The researchers also found that complete removal of the IDH1 gene from mice did not impact the wellness of the animal at the baseline, but made the mice more vulnerable to liver injury at sublethal doses of fat, suggesting partial safety of the treatment.
This finding highlights that the use of Ivosidenib as a cancer therapeutic to inhibit IDH1 in humans to stunt cancer growth—which in the worse case scenario, is akin to removing all the IDH1 genes from the body—may be safe for use in humans.
Given that Ivosidenib is already approved by the FDA for IDH1 mutant cancers, the researchers are optimistic about its approval and use in other IDH1 cancers.
“In our hands and in pre-clinical models, wild-type IDH1 represents a true metabolic vulnerability in cancer cells and is a bona fide therapeutic target across a wide range of wild-type IDH1 cancers,” said Winter.
