A drug used to target IDH1 mutations in certain 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, may become more widely applicable against a variety of cancers, given that the IDH1 mutant is present in only 1% of cancers. The results were recently published in nature cancer.
“Historically, only a few groups have been interested in wild-type IDH1,” said Jordan Winter, MD, chief of the division of surgical oncology at Seidman Cancer Center at University Hospitals (UH) and senior study author. . Dr. Winter is also the John and Peggy Garson Family Chair in Pancreatic Cancer Research and the Jerome A. and Joy Weinberger Family Clinical Master in Surgical Oncology. “Therapeutic research on IDH1 has mainly focused on the development of mutant IDH1 inhibitors. Fewer than a handful of reports have focused on wild-type IDH1 inhibition. We have shown, with a few others, that wild-type IDH1 is an important target. We believe that Ivosidenib, previously called AG-120, may be applicable to the vast majority of cancers – the 1% with mutant IDH1 and the remaining 99% with wild-type IDH1. »
The fundamental observation of this finding is that cancer cells depend on IDH1 metabolism to thrive in a hostile, nutrient-depleted tumor microenvironment. The nutrient limitation universally present in pancreatic tumors could open a new therapeutic window, says the study’s first author, Ali Vaziri-Gohar, PhD, a 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 challenging metabolic environment,” he said. “We discovered that IDH1 is very important for the survival of cancer cells in a stressful microenvironment. When cancer cells have less oxygen and less glucose or glutamine, all of which hurt them, they need a defense mechanism to protect them, which is this important molecule. HDI1. »
In laboratory experiments, Dr. Winter, Dr. Vaziri-Gohar and their colleagues demonstrated that genetic deletion of IDH1 reduced the growth of pancreatic cancer cells in cell culture under low nutrient conditions and in mouse models of pancreatic cancer. They also found that the FDA-approved mutant IDH1 inhibitor, ivosidenib, was surprisingly potent against the wild-type form of the protein, especially when combined with the important low magnesium condition. This last point had been neglected in previous studies.
Dr Vaziri-Gohar said the discovery was a bit of a scientific fluke.
“Initially, we used this drug as a negative control,” he explained. “Then we found that we could use this drug against cancers that have wild-type isoforms if we lowered magnesium levels. We tested this hypothesis in cell culture and found that when magnesium levels reduced in tissue culture, they responded to the inhibitor with and the decrease in enzyme activity. This in turn decreased the survival of cancer cells. However, under normal cell culture conditions with standard magnesium levels found in blood or culture media, they did not respond to this drug. We then realized that magnesium levels were much lower in tumors than in standard culture conditions, so the drug was actually effective against pancreatic cancer and other cancers when given to animals. carriers of these tumours. »
The presence of low magnesium enhanced allosteric inhibition by the drug, and low ambient glucose levels enhanced cancer cell dependence on wild-type IDH1. Thus, two conditions present in the tumors made them susceptible to the drug: low magnesium and low nutrient.
Drs. Winter and Vaziri-Gohar have now tested ivosidenib in mouse models of pancreatic, colorectal, ovarian, and lung cancer, as well as melanoma. In each of these cases, the anti-tumor effect of Ivosdenib was comparable or superior to a previous study of IDH1 mutant anti-tumor treatment. Other drugs developed as mutant IDH1 inhibitors were also effective against tumors without mutations. In the immunocompetent mouse pancreatic cancer model, ivosidenib improved median survival more than two-fold. It was also important for the study that these results be reproduced in a completely separate laboratory, in an experiment carried out on the other side of the Atlantic Ocean. A respected mouse model researcher, Dr Jennifer Morton of the Beatson Institute in Scotland, performed this experiment on a genetically modified mouse that develops pancreatic cancer.
The next step in the team’s research is a clinical trial, made possible with funding from the Cancer Research Gateway and the John and Peggy Garson family. Along with his colleague, Dr. David Bajor, Dr. Winter plans to enroll 15 patients with resectable pancreatic cancer in a Phase I trial of Ivosidenib in combination with the standard treatment, FOLFIRINOX. Patients will receive three months of treatment prior to surgery, assessing their response to treatment by imaging, biochemical blood markers, and ultimately pathology once surgery is complete.
“The primary endpoint is just to determine the safety of the drug with the existing chemotherapy regimen, because it’s never been given together,” said Dr. Winter, who is also a professor in the department of surgery at the Case Western Reserve School of Medicine and a member of the Case Comprehensive Cancer Center’s Developmental Therapy Program, explained. “We are going to compare it to patients who receive chemotherapy before surgery without the Ivosidenib. However, one of the great advantages of this trial is that because all patients will undergo surgery, we will have all tumors to analyze and we will be able to evaluate tumors for the same metabolic changes previously observed in the laboratory. We’re going to look at those same data points, those same response markers in patient tumors to try to demonstrate biological activity inside pancreatic cancer in patients. »
Dr. Vaziri-Gohar says he is grateful for the spirit of collaboration between institutions that has allowed the project to progress so far.
“Beyond the science, it was so rewarding to work with so many people towards a common goal,” he said. “It’s the most important thing for me. That we worked as a team and I hope our discovery will help patients. We are so lucky to have all these researchers and institutions involved. »
Dr. Winter is optimistic about what could be achieved.
“In our hands and in preclinical models, wild-type IDH1 represents a true metabolic vulnerability in cancer cells and is an authentic therapeutic target in a wide range of wild-type IDH1 cancers,” he said. “Mutant IDH1 inhibitors, including FDA-approved ivosidenib, are potent inhibitors of wild-type IDH1 under the conditions found in tumors. Since pancreatic and other tumors share this characteristic, these drugs are compelling investigational agents for these expanded indications. »