Using standard platinum-based chemotherapy is often associated with the formation of unfavorable treatment-resistant cancer stem cells, which may ultimately contribute to cancer progression — but inhibiting an enzyme called NAMPT may be able to prevent this detrimental effect, a study in mice found.
In animal models of ovarian cancer, adding a NAMPT inhibitor to cisplatin treatment not only blocked the outgrowth of chemoresistant stem-like cancer cells. It also delayed tumor relapse and significantly extended survival.
These findings have implications for ovarian cancer patients successfully treated with platinum-based therapies who are at risk for cancer relapse.
The study, “NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer,” was published in the journal Cancer Research.
Platinum-based chemotherapies, such as cisplatin, are the standard-of-care treatment for epithelial ovarian cancer. They work by binding to DNA, blocking cell division, and stopping cell growth — a process known as therapy-induced cell senescence. When cell division is halted, signals are released that trigger the death of the cancer cell.
However, a small population of cancer cells escape senescence and cell death and acquire properties similar to stem cells. Those are a fundamental cell type that can transform into many different cell types.
These transformed cancer stem-like cells (CSCs) secrete a variety of hormones that promote tumor growth — known as the senescence-associated secretory phenotype (SASP) — which is a key driver of cancer relapse and resistance to further platinum-based chemotherapy.
Thus, eliminating the development of CSCs while not affecting the therapy-induced cell senescence and death is a potential therapeutic strategy in the treatment of epithelial ovarian cancer.
The activation of tumor-promoting SASP in these cells is driven by an enzyme called nicotinamide phosphoribosyltransferase (NAMPT). Inhibiting this enzyme was found to suppress SASP without affecting cell senescence.
Although NAMPT represents an ideal target to suppress SASP and selectively eliminate the CSCs that lead to cancer relapse, its role in cell senescence triggered by chemotherapy has not been investigated.
To fill in this knowledge gap, researchers based at the Wistar Institute in Philadelphia designed a study to investigate whether the NAMPT enzyme contributes to the development of CSCs in ovarian cancer following platinum-based chemotherapy. They also tested whether inhibiting NAMPT suppresses tumor growth in cancer cells and in an ovarian cancer mouse model.
The experiments demonstrated that, in cisplatin-treated ovarian cancer cells, NAMPT and its reaction products were significantly elevated. Treating these cells with NAMPT inhibitors reduced the reaction products and lowered the production of SASP tumor-promoting hormones, the experiments showed.
NAMPT inhibition also slowed the growth of ovarian cancer cells, decreased the levels of a stem cell marker identifying CSCs, and induced an increase in markers associated with cell death.
Additionally, these results were replicated in cells isolated and cultured from human ovarian tumor tissues, which demonstrated that NAMPT activity is both necessary and sufficient for therapy-induced CSCs.
Following these findings, the team then investigated whether treating a mouse with a NAMPT inhibitor, which had been transplanted with epithelial ovarian cancer cells and treated with cisplatin, would affect tumor relapse.
Mice that had been given a combination of a NAMPT inhibitor and cisplatin had extended survival times. All mice treated with cisplatin alone died within 100 days of tumor injection, while all animals treated with the combination were alive at the time. The extended survival time was found to be associated with the suppression of CSC development.
“Our studies demonstrate that targeting NAMPT activity through the use of clinically applicable NAMPT inhibitors represents a novel strategy for targeting senescence-associated CSCs in [epithelial ovarian cancer],” the researchers said.
“NAMPT blockage removes the tumor-promoting effects of cellular senescence while not interfering with its tumor-suppressive functions,” Rugang Zhang, PhD, deputy director of the Wistar Institute and senior author on the paper, said in a press release.
“Our findings suggest that clinically applicable NAMPT inhibitors may be applied to enhance the therapeutic effect of cisplatin and improve the platinum-based standard of care in epithelial ovarian cancer,” he concluded.