The drug 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, could become more broadly applicable against a variety of cancers, given that mutant IDH1 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, chief of surgical oncology at University Hospitals Seidman Cancer Center and senior author of the study. Dr. Winter also holds the John and Peggy Garson Family Awarded Chair in Pancreatic Cancer Research and Jerome A and Joy Weinberger as an MSc in Surgical Oncology. “Therapeutic investigations of IDH1 have 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, showed that wild-type IDH1 is an important target. We think that Ivosidenib, previously named AG-120, may be applicable to the vast majority of cancers—one percent with mutated IDH1 and the remaining 99 percent with wild-type IDH1.”
Central to this finding is the observation that cancer cells depend on IDH1 metabolism to thrive in the harsh, nutrient-deprived tumor environment. Study first author Ali Waziri Gohar, PhD, a postdoctoral fellow in the Department of Surgery at Case Western Reserve University School of Medicine, explains that 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 harsh metabolic environment,” he said. “We found 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, anything that harms them, they need a defense mechanism to protect them, which is this important molecule IDH1.”
In laboratory experiments, Dr. Winter, Dr. Waziri Johar and colleagues demonstrated that genetic inhibition of IDH1 reduces pancreatic cancer cell growth in cell culture under low-nutrient conditions and in mouse models of pancreatic cancer. They also found that the FDA-approved inhibitor of mutated IDH1, Ivosidenib, was surprisingly potent against the wild form of the protein — especially when combined with a significant case of low magnesium. This last point has been overlooked in previous studies.
Dr. Waziri Gohar said that this discovery was a scientific coincidence.
“Initially, we were using 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 reduced magnesium levels. We tested this hypothesis in cell culture and saw that when magnesium levels went down in tissue culture, they responded to the inhibitor using and decreased enzyme activity. This in turn reduces the Survival of the cancer cells.However, under normal cell culture conditions with standard magnesium levels present in blood or culture medium, they did not respond to this drug.Then we realized that the magnesium levels in the tumors were much lower than in standard culture conditions, so the drug was actually effective against pancreatic and other cancers when administered to animals harboring 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 sensitive to the drug: low magnesium and low nutrients.
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 anti-IDH1 tumor therapy. Other drugs developed as mutated IDH1 inhibitors similarly have been effective against tumors without mutation. In an immunocompetent mouse pancreatic cancer model, Ivosidenib improved median survival by more than two-fold. It was also important to the study that these results be replicated 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, made possible with funding from Gateway for Cancer Research and the family of John and Peggy Garson. Dr. Winter, along with colleague Dr. David Bajor, plan to enroll 15 patients with resectable pancreatic cancer in a phase I trial of Ivosidenib in combination with the FOLFIRINOX standard of care. Patients will receive three months of treatment prior to surgery, measuring their response to treatment by imaging, blood biochemical markers, and eventually by pathology once surgery is complete.
“The primary end point is only to determine the safety of the drug with the current chemotherapy regimen, because it has never been administered together,” Dr. Winter, who is also a professor in the department of surgery at Case Western Reserve School of Medicine and a member of the Explanation of the Developmental Therapeutics Program at Case Comprehensive Cancer Center. “We will compare it to patients receiving preoperative chemotherapy without Ivosidenib. However, one of the great things about this trial is that because all patients are going to have surgery, we will get all the tumors to analyze and we will be able to evaluate the tumors for the same metabolic changes that were previously observed in the lab. We will look at the same data points, those same markers of response in patients’ tumors to try to establish the biological activity within pancreatic cancer in patients.”
Dr. Waziri Gohar says he is grateful for the spirit of collaboration across institutions that has allowed the project to progress to this point.
“Beyond science, we’ve had the pleasure of working with so many people towards a common goal,” he said. “That’s the most important thing to me. We’ve worked as a team and hope our discovery helps patients. We’re 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 across a wide range of wild-type IDH1 cancers,” he said. “Mutant-IDH1 inhibitors, including FDA-approved Ivosidenib, are potent wild-type IDH1 inhibitors under conditions present in tumors. Because pancreatic and other tumors share this feature, these drugs are compelling research agents for these expanded indications. .”
University Hospitals Cleveland Medical Center
Waziri Gohar, A; Cassell, C. , Muhammed, F and others. The limited availability of nutrients in the tumor microenvironment renders pancreatic tumors sensitive to allogeneic IDH1 inhibitors. Nat Cancer (2222). DOI: 10.1038/s43018-022-00393-y.