Scientists identify key defect in brain tumor cells

In a new study, researchers identified a novel genetic defect that prevents brain tumor cells from repairing damaged DNA. They found that the defect is highly sensitive to an existing FDA-approved drug used to treat ovarian cancer -- a discovery that challenges current practice for treatment of brain tumors and other cancers with the same genetic defect, said the scientists.

The study was published in Science Translational Medicine.

Certain malignant brain tumors and leukemias have mutations in genes known as IDH1 and IDH2, which result in overproduction of 2-hydroxyglutarate (2HG), as observed in multiple tumor types, including gliomas and acute myelogenous leukemia. 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process.'

However, researchers in the current study found that it may be possible to take advantage of 2HG overproduction instead. The researchers tested several existing cancer drugs on the mutated cell lines. They found that tumor cells with the mutant genes were particularly sensitive to a drug, olaparib (PARP inhibitors), recently approved for the treatment of hereditary ovarian cancer. The drug caused a 50-fold increase in brain tumor cell death.

The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, that are already in clinical use.
To better understand this sensitivity, a cross-disciplinary team of researchers created models of the mutation in cell cultures.

These findings run counter to current practices in oncology. "Our work at Yale has practice-changing implications, as our data suggest an entirely new group of tumors can be targeted effectively with DNA repair inhibitors, and that possibly these patients currently are not being treated with the most optimal approaches," said senior author.

Co-senior author noted, "Our work raises serious caution regarding current therapeutic strategies that are aimed at blocking mutant IDH1 and IDH2 protein function, as we believe the DNA repair defect should be exploited rather than blocked."

Based on these studies, the authors are designing a clinical trial to test whether DNA repair inhibitors, such as olaparib, are active against IDH1- and IDH2-mutant tumors. They anticipate that this trial will be open for enrollment later in 2017.