In findings that show a way to target tumors with mutations in isocitrate dehydrogenase 1 (IDH1), as well as bring new insights into the complexity of its effects, researchers have discovered that inhibiting cell cycle checkpoints or the DNA damage response could be a treatment option for gliomas with IDH1 mutations.

The team showed that treatment with the checkpoint inhibitor AZD7762 or the ATM kinase inhibitor KU60019, which targets both cell cycle checkpoints and DNA damage repair, sensitized tumors with a specific combination of three mutations that included the IDH1(R132H) mutation in both genetically engineered mouse models and patient-derived xenografts.

The findings, appeared in the Feb. 13, 2019, issue of Science Translational Medicine.

IDH1 is an enzyme with multiple effects on the cellular level, and its effects on clinical outlook are correspondingly complex.

IDH1 catalyzes the formation of 2-hydroxyglutarate (2HG), and elicit what Maria Castro, professor of neurosurgery and of cell and developmental biology at the University of Michigan and co-corresponding author of the paper, called "profound reprogramming. Mutations in this metabolic enzyme elicit the reprogramming of the metabolic response, DNA damage response, and renders cells resistant to radiotherapy," she told BioWorld.

The goal of the study was to understand "the pathway from this mutation to resistance," co-corresponding author Pedro Lowenstein, who is also a professor of neurosurgery and of cell and developmental biology at the University of Michigan, told BioWorld.

The team looked at mice with multiple mutations. In addition to the IDH1 mutation, they had inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) as well as the IDH1(R132H) mutation, making their tumors a model of astrocytomas.

The team showed that the combination of three mutations led to increased activity of homologous recombination repair, which protected them from the DNA damage through which radiation kills tumor cells.

Hurry up and divide already!

To repair themselves, cells "need good cell cycle checkpoints, because [cell cycle progression] needs to stop," Lowenstein explained. Because of their rapid growth, tumor cells are typically sensitive to DNA damage because they speed through the cell cycle.

But in the animal model developed by the Michigan team, "the cell cycle is highly functional – when you irradiate, the cells just stop their cell cycle, repair themselves, and carry on."

Treatment with cell cycle checkpoint inhibitors or DNA damage response inhibitors, though, rendered the cells sensitive to radiation therapy.

In 2018, IDH1 inhibitor Tibsovo (ivosidenib, Agios Pharmaceuticals Inc.) was approved, along with a companion diagnostic, for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH1 mutation. (See BioWorld, July 23, 2018.)

However, IDH mutations also appear to render cells vulnerable to PARP inhibitors, and some researchers argue that exploiting that vulnerability is a more promising approach. (See BioWorld, Feb. 2, 2017.)

To Castro, the moral of the story is that context matters.

"Controversy arises when people do experiments in different model systems," she said. "What our paper shows is that you have to study [IDH1] in the context of other genetic lesions."

She said the work marks "the generation of the first [glioma] animal models with combination of mutations," a feat that will hopefully contribute to the development of precision-based glioma treatments.

Lowenstein added that inhibiting IDH1 and exploiting the vulnerabilities it confers are "not mutually exclusive – we have other projects that are looking at IDH inhibition."

The team is also working on understanding why the IDH1 mutations confer a survival advantage, in hopes of extending that survival.

Compared to many other brain tumors, patients with IDH1-driven tumors "live much longer," Lowenstein said – after the initial treatment, remissions of seven to 10 years are typical.

Ultimately, though, those patients "still die," he said. "The tumor always comes back, and when it comes back, it comes back as a high-grade glioma," and survival is a matter of months, not years.

"Exactly how the [survival advantage] works is not precisely understood," Lowenstein said. There must be things that are intrinsic to the structure of the tumors... that don't allow them to become malignant so quickly."

Even when such tumors eventually do become malignant, they still express the mutated IDH1, leading Lowenstein, Castro and their colleagues to conclude that "there are genes that override the effects of mutants," he said.

Targeting those override signals might be a way to extend survival of patients with IDH1 mutant tumors. In the best case, it could transform IDH1-driven brain cancer into a chronic disease, he said: "We are looking for those genes."