A new study led by Yale Cancer Center scientists revealed the combination of ATR and PARP inhibitor therapies can effectively target the enzyme isocitrate dehydrogenase-I/2 (IDH-1/2) in mutant cancer cells. The findings could help minimize toxicities from drug treatment for patients with cancer. The research is published online in the journal NAR Cancer.
“Mutations in IDH1/2-mutant cancers were first identified in glioma, acute myeloid leukemia (AML), and subsequently found in multiple other tumor types,” said lead study author Amrita Sule, PhD, a postdoctoral associate in the laboratory of Ranjit S. Bindra, MD, PhD, Professor of Therapeutic Radiology at Yale Cancer Center. “These findings demonstrate the efficacy of targeting these defects to help develop new treatments for patients.”
Previous studies from the Bindra Lab and others have showed that cancer cells with mutations in the gene IDH-1/2 cannot repair their DNA efficiently. PARP inhibitors are effective in killing these cells due to increased unrepaired DNA. However, patients treated with PARP inhibitors often develop resistance, creating the need to develop alternate therapies.
Combined inhibition of ATR and PARP is synergistic by blocking central, but independent, DNA-repair pathways. ATR is a protein which keeps the cell cycle in check when the DNA is damaged. It ensures the cells only divide when the DNA is repaired correctly. In this study, researchers confirmed when PARP inhibitors are combined with ATR inhibitors, the cell death of IDH -1/2 cancer cells is enhanced compared to a PARP inhibitor alone.
In mechanistic studies, researchers observed that inhibiting PARP and ATR causes the IDH1-1/2 mutant cells to accumulate unrepaired DNA, leading to increased genomic instability and ultimately destruction. This combination was also tested in mice seeded with IDH-1/2 cancer cells. The combination of PARP inhibitor (Olaparib) and ATR inhibitor (AZD6738) was well tolerated in laboratory studies and caused significant tumor shrinkage as opposed to when the mice were given the single drug. Currently, this combination is being evaluated in a clinical trial with patients with IDH1-2 mutant solid tumors in a National Cancer Institute phase II trial.
“We continue to seek novel targets for IDH -1/2 and similar cancers and carry out pre-clinical studies, which can lay the groundwork for future clinical trials,” added Bindra, senior author of the study.
This study was supported by grants from AACR-START, the National Institutes of Health, and pilot funding from the National Brain Tumor Society.
Other Yale authors for the study include Jinny Van Doorn, Ranjini K. Sundaram, PhD, Sachita Ganesa, and Juan C. Vasquez.