"We think PROX1 is regulating the androgen receptor," Alumkal explained. "It may be one explanation for why the androgen receptor gets turned off when tumors undergo lineage plasticity and transition away from the typical glandular prostate cancer identity."
This shift in identity is a survival mechanism for the cancer, but the Michigan team discovered that it also creates a new vulnerability. When the researchers used genetic methods to eliminate PROX1 expression in both double-negative and neuroendocrine prostate cancer cells, the results were dramatic. The cancer cells stopped proliferating and began to die. This indicated that while the cells had escaped their need for the androgen receptor, they had become "addicted" to PROX1 to maintain their new, aggressive identity.
However, translating this discovery into a clinical treatment presented a classic hurdle in drug development. Transcription factors like PROX1 are notoriously difficult to target directly with medication because they often lack the deep, well-defined "pockets" that traditional drug molecules need to bind to. To find a workaround, the researchers looked at the "company PROX1 keeps"—the other proteins it interacts with to carry out its functions.
"We examined the proteins that bind to PROX1," Alumkal said. "Among the top partners were histone deacetylases, or HDACs. We felt like this was guilt by association. We hypothesized that HDACs might cooperate with PROX1 and that targeting HDACs might be like targeting PROX1."
Histone deacetylases are enzymes that influence how DNA is packaged within a cell, thereby controlling gene expression. Because HDACs are already known to play roles in various types of cancer, the pharmaceutical industry has already developed several HDAC inhibitors. A number of these drugs have already received approval from the U.S. Food and Drug Administration (FDA) for treating certain blood cancers, though they have not yet become a standard of care for prostate cancer.
When the Rogel Cancer Center team tested HDAC inhibitors on prostate cancer cells expressing high levels of PROX1, the results confirmed their hypothesis. The cells were highly sensitive to the drugs. Treatment with HDAC inhibitors effectively depleted the PROX1 protein within the cells, leading to tumor cell death. The effect of the drugs was nearly identical to the results achieved when the researchers genetically removed the PROX1 gene entirely.
