Targeting Ovarian Cancer With Combination of PARP Inhibitors and Senolytic Agents
Posted: Monday, July 8, 2019
Preclinical models suggest that a combination of PARP inhibitors and senolytic drugs may prove to be effective in the treatment of ovarian cancer and may ultimately limit drug resistance. A research team including Francis Rodier, PhD, of the University of Montreal, Canada, and colleagues published its study in Nature Communications.
“First, we force the cancer cells to age prematurely (ie, we force them into senescence). This is the first therapeutic punch. We throw our second punch using senolysis, destroying and eliminating them,” explained Dr. Rodier in an institutional press release.
Using a combination of cell culture, flow cytometry, immunofluorescence, and murine xenografts, researchers evaluated their two-step therapy. Olaparib was used to treat ovarian cancer cells first. Olaparib-treated ovarian cancer cells were found to develop a senescence-like state that is mediated by p21 and Chk2, independent of p53. However, this senescence was reversible, possibly explaining the rapid therapy resistance/recurrence in ovarian cancers.
Genes in the antiapoptotic BCL2 family were identified as working synergistically with PARP inhibitors in the context of senescence. Senolytic drugs such as ABT-263 (also known as navitoclax) were able to take cancer cells in this senescence-like state and induce apoptosis. Researchers translated this evidence into in vivo models and found that there were lethal interactions between PARP inhibitors and senescent cancer cells.
“Our approach could improve the effectiveness of chemotherapy in combination with PARP inhibitors and counteract the systematic resistance that develops with this treatment,” said coauthor Anne-Marie Mes-Masson, PhD, also of the University of Montreal, in an institutional press release.
Disclosure: The study authors reported no conflicts of interest.