In recent years laboratory studies using AMPI-109 — a novel alkylating analog of vitamin D — have shown the experimental therapy is a potential killer of triple-negative breast cancer cells. But no matter how positive the results in the lab, anti-tumor drugs can only be included in a human clinical trial when researchers know their mechanisms of action.
A recent study now proposes that AMPI-109 exerts its protective effect by regulating the activation of the PRL-3 gene, which encodes an enzyme (with the same name) that controls the activation or senescent (sleep) state of cancer cells.
The study, “Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth,” was published in the journal Oncogenesis.
“With this gene active, cells survive. With PRL-3 inactivated, cells senesce and eventually die,” said study author Hamid Gari, PhD, in a news release.
The researcher explained that, when active, PRL-3 regulates several genes that allow cancer cells to hide from the immune system, helping them multiply when conditions are favorable, and to “sleep” when conditions are less favorable (as in anti-cancer therapies, for example).
The authors said using genetic tools or AMPI-109 to inactivate the PRL-3 gene in triple-negative breast cancer cells had the same effect: the death of cancer cells. They believe that, by shutting down the PRL-3 gene, AMPI-109 forces cancer cells to stay inactive for a longer time, which eventually leads to their detection and elimination by the immune system.
“Our studies propose that by inhibiting PRL-3 activity, such as with AMPI-109, it may serve as a ‘flag’ to signal the immune system where the tumor is, and in essence could sensitize tumors to immunotherapy,” Gari said. “The result is a two-hit strategy to expose the tumor and then allow the immune system combat it.”
This is an important finding, given that many cancer types can effectively hide from the immune system and therefore, certain therapies are engineered to avoid the progression of cancer instead of killing it completely.
Additional studies on the potential beneficial effect of AMPI-109 may help understand whether this drug could possibly become an effective therapy for triple-negative breast cancer and enter a human clinical trial.