Researchers at the University of Colorado report new insights into an experimental drug named AMPI-109. They found that AMPI-109 flips the switch on an enzyme called PRL-3, inactivating cancer cells from growing and leading to their death.
Breast cancer often expresses the genes of estrogen receptor (ER), progesterone receptor (PR), or Her2, and chemotherapy-based treatments are usually designed to target one of these receptors. But triple-negative breast cancer (TNBC) does not express any of these receptors, which makes it challenging to treat and often requires combination therapies.
Researchers at the University of Colorado Cancer had previously demonstrated that AMPI-109 potently eliminates TNBC cells. However, the drug did not move into human clinical trials because researchers did not understand how the drug worked — its mechanism of action — which is required for clinical trials.
In this study, researchers gained a better understanding of how AMPI-109 works by demonstrating that the enzyme PRL-3 plays an important role. They found that PRL-3 controls certain genes involved in the immune system by either helping cancer cell growth during certain periods or inhibiting them during other periods, such as when anti-cancer therapies were administrated.
“For decades, we’ve known about a paradoxical signaling pathway called TNF-R1 whose activation can either help a cell survive or lead to cell death,” Hamid Gari, PhD, a doctoral candidate at Colorado University Cancer Center, said in a press release. “However, the signals that lead to this pathway promoting survival or promoting death have been poorly understood, especially in the context of cancer cells. We have observed that one regulator of this process in triple-negative breast cancer cells may be the activity of PRL-3. With this gene active, cells survive. With PRL-3 inactivated, cells senesce [sleep] and eventually die.”
“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. The result is a two-hit strategy to expose the tumor and then allow the immune system to combat it,” Gari added.
The researchers believe that these results are important, especially as cancer immunotherapies become first-line treatments. If these results remain promising, AMPI-109 could significantly impact treatment of TNBC.
Researchers are applying for funding from NIH and other sources to investigate the drug’s safety and efficacy.