One of the drugs used to target IDH1 mutations in some cancers also appears to inhibit the wild form of the enzyme, under certain conditions. This feature explains why a wide range of different cancers are exposed to the drug. This finding opens the possibility that the drug, Ivosidenib or AG-120, may become more applicable to a variety of cancers, given that the IDH1 mutation 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 surgical oncology at University Hospitals Seidman Cancer Center (UH) and senior author of the study. Dr. Winter is also the John and Peggy Garson Family Head of Pancreatic Cancer Research and Jerome A and Joy Weinberger’s Family Clinical Masters in Surgical Oncology. Therapeutic research on IDH1 has mainly focused on the development of mutant IDH1 inhibitors. Less than a few reports have focused on the inhibition of wild-type IDH1. We, along with a few others, have shown that wild-type IDH1 is an important target. We believe that Ivosidenib, previously named AG-120, may be applicable to the vast majority of cancers – 1% with mutant IDH1 and the remaining 99% of wild-type IDH1. »
The fundamental observation of this finding is that cancer cells depend on IDH1 metabolism to thrive in an anti-tumor and nutrient-deficient microenvironment. The study’s first author, Ali Waziri Gohar, MD, a postdoctoral fellow in the Department of Surgery at Case Western Reserve University School of Medicine, says the limitations of nutrients globally found in pancreatic tumors could open a new therapeutic window.
“Wild-type IDH1 activity is a metabolic requirement for cancer cells that live 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 harm them, they need a defense mechanism to protect them, which is this important molecule HDI1.”
In laboratory experiments, Dr. Winter, Dr. Waziri Johar and their colleagues demonstrated that genetic deletion of IDH1 reduces 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, ifodinib, was surprisingly effective against the wild form of the protein, especially when combined with a significant low magnesium condition. This last point has been neglected in previous studies.
Dr. Waziri Gohar said that this discovery was just a scientific coincidence.
“Initially, we used this drug as a negative control,” he explained. Then we found that we could use this drug against cancers with wild-type isoforms if we lowered our magnesium levels. We tested this hypothesis in cell culture and found that when Mg levels decrease in tissue culture, they respond to the inhibitor with decreased enzyme activity. This in turn reduces the survival of cancer cells. However, under normal cell culture conditions with standard magnesium levels in blood or culture medium, 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 types of cancer when given to animals, who are carriers of these tumors. »
The presence of low magnesium enhanced the allosteric inhibition by the drug, and low ambient glucose levels enhanced the dependence of cancer cells on wild-type IDH1. Thus, two conditions present in the tumors made them susceptible to the drug: low magnesium and low nutrient.
Dr.. 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 antitumor effect of Ivosdenib was similar or superior to a previous study of mutated IDH1 antitumor therapy. Other drugs developed as mutated IDH1 inhibitors were also effective against tumors without mutations. In an immunocompetent mouse pancreatic cancer model, ifodinib improved the median survival rate more than doubled. It was also important for the study to reproduce these results in a completely separate laboratory, in an experiment conducted on the other side of the Atlantic. Respected mouse model researcher Dr Jennifer Morton of the Bateson Institute in Scotland conducted this experiment on a genetically modified mouse that develops pancreatic cancer.
The next step in the team’s research is a clinical trial, which was made possible by funding from the Cancer Research Gateway and the family of John and Peggy Garson. Dr. Winter, along with his colleague, Dr. David Bajor, plan 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 eventually pathology once surgery is complete.
Winter, who is also a professor in the department of surgery at Case Western Reserve School of Medicine and a member of the Developmental Therapy Program at Case Comprehensive Cancer Center, explained. “We will compare it to patients receiving preoperative chemotherapy without Ivosidenib. However, one of the great advantages of this trial is that since all patients will have surgery, we will have all tumors to analyze and we will be able to evaluate tumors for the same metabolic changes observed previously in the lab. We’ll look at the same data points, the same response markers in patients’ tumors to try to establish the biological activity within patients’ pancreatic cancer.”
Dr. Waziri Gohar says he is grateful for the spirit of collaboration between the institutions that has allowed the project to progress so far.
“Beyond the science, it has been very rewarding to work with so many people towards a common goal,” he said. “It’s the most important thing to me. We worked as a team and I hope our discovery helps patients. We are very fortunate to have all these researchers and institutions involved.”
Dr. Winter is optimistic about what can be achieved.
“In our hands and in preclinical models, wild-type IDH1 represents a true metabolic vulnerability in cancer cells and is a real 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 conditions present in tumors. Because pancreatic and other tumors share this characteristic, these drugs are compelling research agents for these extended indications. »
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