We’ve known this for decades: some prostate cancer cells respond to androgens (male hormones), and some don’t. This is why androgen deprivation therapy (ADT), although “an extremely targeted and highly effective treatment for prostate cancer,” is not a cure, says Shawn Lupold, Ph.D.: because it doesn’t stop the cancer cells that aren’t affected by androgens. Even when the androgen-dependent cells are under control, these other cells keep right on growing and dividing. Eventually, the balance tips, and ADT is no longer enough to keep the cancer in check; this is called castration-resistant prostate cancer (CRPC).

Lupold, looking at different targets for treatment, has been studying genes activated by the androgen receptor (AR). An androgen such as testosterone binds to an AR like a key in a lock. This, in turn, “activates” the AR, “allowing it to enter the nucleus of the cell, bind DNA, and activate a large number of genes,” Lupold explains. “This pathway is exceedingly critical for prostate cancer cells.” In CRPC, androgen-resistant cancer cells can make use of the AR pathways – which are supposed to be shut down – through tricky genetic maneuvers: imagine a crook jimmying a lock or making a skeleton key. These genetic alterations “allow cancer cells to use androgen-like molecules, or low levels of androgens, to re-activate the pathway. In fact, some tumors even evolve mechanisms to produce their own androgens.” Pretty sneaky!

In sophisticated, painstaking research that took more than a decade, Lupold and colleagues set out to find the particular AR genes that promote prostate cancer cell survival and castration resistance. They began by looking at newly discovered genes called microRNAs (MiRNAs). Unlike most genes, microRNAs do not make proteins; instead, they are troublemakers that prevent a gene’s protein from being made. Imagine you go into a diner and order a grilled cheese sandwich; the waitress writes your ticket and sends it to the short-order cook – but before the ticket reaches the kitchen, somebody tears it up! That’s what MiRNAs do on a genetic level: they tear up tickets. Lupold and colleagues zeroed in on one particular microRNA called miR-21. “We discovered that elevated levels of miR-21 could stimulate prostate cancers to develop castration resistance.” This discovery, led by Judit Ribas and published in Cancer Research in 2009, “set us on a new journey: to determine how miR-21 drives castration resistance.” Specifically: which gene did miR-21 use to accomplish its mischief?

A postdoctoral fellow in Lupold’s lab, Fatema Rafiqi, using complex computer algorithms, sifted through thousands of genes and analyzed likely candidates with Ross Liao, now a Johns Hopkins medical student. Postdoctoral fellow Koji Hatano identified a likely suspect: PDCD4 (Programmed Cell Death 4), a tumor suppressor gene. Postdoctoral fellow Kenji Zennami began studying this gene in prostate cancer cell and tumor models, in work he and Lupold’s lab recently published in Molecular Cancer Research.

“We found that androgens significantly reduced PDCD4 production in prostate cancer cells, and that ADT or AR inhibition (androgen receptor-blocking drugs such as enzalutamide) triggered PDCD4 expression. This activity was reduced when we blocked miR-21, providing a direct link between the AR, miR-21, and PDCD4.” When they shut down PDCD4, prostate cancer cells multiplied – and cancer cell death slowed. “Like miR-21 over-expression, PDCD4 inhibition caused prostate cancer cell growth and hormone resistance.” These results were so striking that Lupold believes PDCD4 may be a gatekeeper for prostate cancer’s response to ADT. He sees PDCD4 as a key “thermostat” for prostate cancer, whose presence or absence helps determine whether the cancer cells will die, or go on to become independent of hormonal control.

“We don’t yet understand how PDCD4 regulates prostate cancer cell proliferation or androgen sensitivity,” Lupold adds. “Further studies are required to solve this puzzle.” In the meantime, PDCD4 has the potential to be a new biomarker for higher-risk patients. “Preliminary studies from human prostate tissues indicate that PDCD4 levels are lower in more-aggressive cancer (high Gleason grade).” The next steps are to determine whether PDCD4 also has the potential to become an entirely new mode of treatment for high-risk or advanced prostate cancer.