PARP Inhibitors May Be Effective in Brain, Other Cancers with IDH Mutations

April 24, 2017, by NCI Staff

Illustration of an enzyme encircling a strand of DNA — PARP enzymes help repair damaged DNA. PARP inhibitors block this repair mechanism, causing some cancer cells to die.

Credit: NIGMS / Tom Ellenberger, Washington University School of Medicine

Two separate studies have revealed new insights into the function of genetic mutations commonly found in a form of brain cancer as well as several other cancers and, in the process, identified a potential new treatment strategy.

The studies showed that cancer cells with these mutations, which affect a gene called IDH, have an impaired ability to repair DNA damage. Treating these cells with PARP inhibitors, drugs that further disrupt DNA repair, effectively killed the cells, the researchers reported at the 2017 American Association for Cancer Research (AACR) annual meeting.

Although low-grade gliomas that have an IDHmutation are typically more sensitive to chemotherapy than those that lack the mutation, the disease tends to come back as a more aggressive tumor after treatment, explained Chun Zhang Yang, Ph.D., of the Neuro-Oncology Branch in NCI’s Center for Cancer Research and lead investigator for one of the studies.

Two independent research groups—one led by Dr. Yang and another by Ranjit Bindra, M.D., Ph.D., of Yale School of Medicine—set out to investigate why IDH-mutant gliomas are more vulnerable to chemotherapy and whether amplifying this vulnerability can kill more glioma cells.

Both groups found that IDH mutations weaken the ability of glioma cells to repair DNA. Moreover, they found, this weakness can be exploited with the use of PARP inhibitors. The Yale researchers showed that PARP inhibitors killed glioma cells with IDH mutations but not cells with normal IDH. And a PARP inhibitor enhanced the toxic effects of chemotherapy treatment on IDH-mutant cells, the NCI team reported.

The NCI team previously reported the results of their study in Cancer Research and the Yale group previously published their findings in Science Translational Medicine.

Enhancing DNA Damage

Some cancer therapies, like chemotherapy and radiation, damage DNA. If the damage is not extensive, cells can often repair it and carry on. But if cells have defects in their ability to repair DNA, they may not be able to recover and will usually die.

For example, ovarian cancer cells with certain mutations in the BRCA1 or BRCA2 genes have reduced DNA-repair abilities. Research has shown that these cells are especially sensitive to the effects of PARP inhibitors, such as olaparib (Lynparza™), which is approved by the Food and Drug Administration to treat some women with BRCA-mutant ovarian cancer.

Now the NCI and Yale research groups have shown that certain mutations in the IDHgenes may present the same therapeutic opportunity in gliomas, and potentially other cancers, as BRCA mutations do in ovarian cancer.

IDH1 and IDH2 are enzymes that normally generate molecules needed for cell metabolism. The mutant IDH enzymes found in gliomas and other cancers, however, have the novel ability to produce an unusual molecule, called 2-HG. 2-HG has many varied effects on cell biology, though it’s precise link to the development of some cancers has been unclear. Mutations that give genes a new function are called "neomorphic."

In their study, Dr. Bindra's team found that several cancer cell lines with neomorphic IDHmutations had reduced DNA-repair abilities. Additional experiments showed that 2-HG may be responsible for this defect: adding 2-HG to cancer cell lines with normal IDHsuppressed their ability to repair DNA.

Because cells with defects in DNA repair have increased sensitivity to drugs that further block DNA repair, the Yale researchers treated human glioma cells with olaparib and found that IDH1-mutant cells were indeed more sensitive to the PARP inhibitor than cells with normal IDH1.

And in mice bearing IDH1-mutant colon or cervical cancer xenograft tumors, olaparib slowed tumor growth better than a control treatment. Olaparib did not affect the growth of colon or cervical cancer tumors with normal IDH.

On the other hand, they found that treating IDH-mutant colon or cervical cancer cells with drugs that block the production of 2-HG by mutant IDH enzymes (called IDH inhibitors) reversed the DNA-repair defect and made the cells insensitive to PARP inhibitors.

These data support the idea that, for cancers with neomorphic IDH mutations, PARP inhibitors may be more effective than IDH inhibitors, Dr. Bindra said at the AACR press briefing where he presented his group’s findings. IDH inhibitors are being tested in clinical trials as a potential treatment option for patients with IDH1-mutant glioma, he noted.

The "reflex approach for oncologists" has been to block oncogenes, mutated genes that drive cancer growth, said Louis M. Weiner, M.D., director of the Georgetown Lombardi Comprehensive Cancer Center, who moderated the press briefing. Because IDHmutations act like oncogenes, the assumption has been that they should be blocked, Dr. Bindra explained.

"These data suggest that…the correct way is not to think that all mutations should be inhibited, but that there are mutations that create vulnerabilities that can be exploited," Dr. Weiner added.

At the AACR meeting, Yanxin Lu, Ph.D., of NCI's Neuro-Oncology Branch, presented similar evidence from the NCI group's study on the activity of PARP inhibitors in IDH-mutant gliomas.

They found that temozolomide, the standard treatment for patients with glioma, generated more DNA damage and killed more glioblastoma cells with IDH1 mutations than those with normal IDH. Additional experiments showed that IDH1-mutant glioblastoma cells have alterations in their metabolism that prevent effective DNA repair. When they treated IDH-mutant glioblastoma cells with olaparib and temozolomide, they found that olaparib enhanced the DNA-damage and killing effects of temozolomide.

"Our study has shed light on this combination therapy as a future direction for clinical therapy of low-grade gliomas," said Dr. Yang. A similar combination therapy strategy may work for other cancer types with DNA repair deficiencies, he added.

On to Clinical Trials

Dr. Bindra and his colleagues are developing an NCI-sponsored phase II clinical trial of olaparib in patients whose cancers have neomorphic IDH mutations, he announced at the AACR meeting. In addition to gliomas, neomorphic IDH mutations are found in acute myeloid leukemia, liver cancer, colorectal cancer, and several other cancers.

The researchers expect to start enrolling patients later this year and will use the DNA-sequencing technology being used in the NCI-MATCH study to assess and identify patients whose cancers have a neomorphic IDH mutation.

Based on their own work and related studies, Dr. Bindra and his colleagues are hopeful that 2-HG may act as a biomarker for cancer cells that are sensitive to treatment with PARP inhibitors. They plan to measure 2-HG levels in participants’ tumors to determine whether they correlate with a response to olaparib.

Dr. Yang and his colleagues at NCI are also designing a clinical trial of olaparib and temozolomide in patients with low-grade gliomas.

Although nearly 80% of patients with low-grade gliomas have a neomorphic IDHmutation, olaparib may have a limited ability to cross the blood–brain barrier and reach these tumors, Dr. Bindra noted.

However, preliminary evidence from an ongoing clinical trial of olaparib and temozolomide in patients with relapsed glioblastoma suggests that olaparib can penetrate some glioblastoma tumors, he said. Less is known about whether olaparib may penetrate low-grade gliomas, he added. That trial, led by Professor Anthony Chalmers, Ph.D., of the University of Glasgow, is currently recruiting participants.