WASHINGTON – Researchers at Yale University have received conditional approval for a clinical trial that will test whether isocitrate dehydrogenase (IDH)-mutated tumors might respond better to poly-ADP ribose polymerase (PARP) inhibitors than to IDH inhibitors.
"If we see an oncogene, our reflexive thought is to block it," Ranjit Bindra told reporters at the 2017 annual meeting of the American Association for Cancer Research (AACR).
Bindra, who is an assistant professor of radiotherapy at Yale University School of Medicine, and his colleagues are trying to convince their colleagues that such blockade is not always the best way to deal with oncogenes.
There's a pertinent example for his theory. "You don't see a whole industry around developing BRCA inhibitors," Bindra noted.
The comparison is apt because in a situation analogous to that of BRCA mutations, IDH-mutated tumors are bad at repairing their DNA.
The oncometabolite produced by mutant IDH, 2-hydroxyglutarate (2HG), impairs one of the cellular DNA damage response pathways of the cell.
Earlier this year, Bindra and his colleagues published preclinical work showing that like BRCA-mutated tumor cells, IDH-mutated cells are very vulnerable to PARP inhibitors Lynparza (olaparib, Astrazeneca plc) and Rubraca (rucaparib, Clovis Oncology Inc.). (See BioWorld Today, Feb. 2, 2017.)
In that paper, they also showed that treatment with IDH inhibitors, by lowering 2HG levels in the cell, reversed the cells' sensitivity to PARP inhibitors, causing Bindra to speculate that treatment with IDH inhibitors might actually backfire.
IDH mutations are found in various cancers, and the trial, which will open later this year, will be run as a basket trial. Such trials allow patients with the mutation to enter regardless of the anatomical location of their tumors.
Other research presented at the conference has shown that anatomical location affects tumors' sensitivity to drugs, either due to epigenetic or microenvironmental differences. (See BioWorld Today, April 4, 2017.)
Bindra said that the team would be looking at patient subgroups to see whether some tumor types responded better than others.
There might be complementary roles for IDH and PARP inhibition. IDH is clearly a driver gene in the onset of IDH-mutated tumors, switching to a passenger role later in the course of the disease. Patients diagnosed before that switch could benefit from IDH inhibitors.
Bindra, though, is skeptical of a role for IDH inhibitors. He acknowledged that in principle, there is an early stage where such inhibitors might be useful – but said that "most of these patients are diagnosed pretty late."