PARP-7 Amplification Mutations Linked to Prolonged Survival in Ovarian Cancer

PARP-7 amplification mutations are associated with prolonged survival among patients with platinum-sensitive ovarian cancer. Furthermore, PARP-7 might facilitate the paclitaxel sensitivity of these tumors, according to preclinical research (abstract 18) presented at the 2018 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held March 24–27 in New Orleans, Louisiana.

Poly (ADP-ribose) polymerases (PARPs) are a 17-member family of enzymes that transfer ADP-ribose to target proteins. Their biological functions are incompletely understood, but ovarian cancers overexpress PARPs.

The US Food and Drug Administration (FDA) has approved the PARP inhibitors olaparib, rucaparib, and niraparib for patients with ovarian cancer. Olaparib and rucaparib are FDA-approved for patients with recurrent ovarian cancer harboring BRCA mutations following at least three and at least two lines of chemotherapy, respectively.

In 2017, the FDA also approved olaparib for maintenance treatment of recurrent ovarian cancer with partial or complete response to platinum-based chemotherapy regardless of BRCA mutation status.

“There are only these PARP-1, PARP-2, and PARP-3 inhibitors,” noted Lavanya H. Palavalli Parsons, MD, of the University of Texas Southwestern Medical Center in Dallas.

All PARP-7 genomic alterations in ovarian cancers involve gene amplification mutations, Parsons said. It is unknown whether PARP-7 is active in the cell nucleus or the cytoplasm. It might be involved in antiviral responses, RNA processing, or gene transcription.

“PARP-7’s biological function is very uncertain,” Parsons cautioned.

An analysis of The Cancer Genome Atlas (TCGA) suggests that PARP-7 alterations are associated with better overall survival (OS) among patients with ovarian cancer, particularly those with platinum-sensitive disease (mean OS, 36 months vs 14.7 months P = < .01).

The research team produced a protein called PARP-7 to explore the proteomics of the PARP-7 enzyme and to identify its molecular substrates. They found that most PARP-7 targets exist in the cellular cytoskeleton and suspect that it is involved in cellular division and movement.

“It’s clear that PARPs have more roles than repairing DNA damage,” Parsons said.

Taxanes target cellular tubulin and the microtubule system, and because carboplatin plus paclitaxel is a primary treatment for treating ovarian cancer, the authors reason that increased amplification of PARP-7 might facilitate paclitaxel sensitivity, explaining the association between PARP-7 expression and prolonged OS.

In 2018, an estimated 22,240 Americans will be newly diagnosed with ovarian cancer, the 5th leading cause of cancer deaths for women. Eight in 10 women with advanced ovarian cancer will experience disease recurrence following primary treatment.