A new imaging method aims to identify ovarian cancer patients most likely to benefit from treatment with PARP-1 inhibitors — a drug class being developed for people with mutations in the BRCA1 gene.
Researchers at the University of Pennsylvania’s Perelman School of Medicine presented their study, “Exploring the significance of PARP-1 expression for therapy and clinical PET/CT imaging of PARP-1 in ovarian cancer,” at the 2017 American Association for Cancer Research Annual Meeting, held April 1-5 in Washington, D.C.
PARP-1 is an enzyme that repairs broken DNA strands. BRCA is also involved in DNA repair, and mutations in these genes are common in ovarian cancer. But in ovarian cancers with mutated BRCA genes, the tumor often relies on PARP-1 for survival. So, in theory, blocking PARP-1 would make a tumor more prone to die from damage caused by DNA-destroying drugs.
Since UPenn researchers didn’t know whether the enzyme is active in any particular tumor, they developed a new type of positron emission tomography (PET) imaging to solve the issue. PET uses a radioactive tracer to image structures within the body, and a new tracer allowed them to see the active enzyme.
“Research exists that shows PARP inhibitors can be effective in the treatment of BRCA1 mutated cancer, but there are no good existing methods to explore how mutations within BRCA genes affect PARP-1 expression,” Mehran Makvandi, PharmD, RPh, the study’s lead author, said in a press release. “We wanted to validate our radiotracer technology as a quantitative biomarker for PARP-1 with the goal of selecting patients who could benefit from PARP inhibitor therapy.”
Using ovarian cancer cells, with and without BRCA1 mutations, they removed PARP1 with the help of gene editing. They then treated the cells with PARP-1 inhibitors and a chemotherapy drug. Then they repeated the experiments in cells with BRCA1 mutation and intact PARP-1.
“We were able to compare the effects of losing PARP-1 to the effects of gaining BRCA1,” Makvandi said. “For a lot of the PARP inhibitors, losing PARP-1 led to as much or even more resistance to the treatment as the restoration of BRCA1 function. Furthermore, sensitivity to PARP inhibitors was reflected in the measures of PARP-1 expression provided by our new radiotracer method. ”
The team then validated the imaging method in patients with epithelial ovarian cancer.
“PARP-1 expression has had only limited evaluation as a predictive biomarker for PARP inhibitor therapy, in part due to the lack of good tools for measuring levels in patients. We now have a technology that will allow us to clinically assess PARP-1 in a non-invasive way,” Makvandi said.
But the imaging method can be used for more than simply identifying the patients most likely to benefit from treatment with PARP-1 inhibitors. It can also be used to assess if the treatment is working. “We can quantify PARP-1 at baseline, and then use serial imaging studies to directly measure the effects of PARP inhibitors,” Makvandi said.
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