Androgen Deprivation Therapy and Radiation: A Synergistic Effect

There is a saying from the world of computer programming: “Theory is when you know something, but it doesn’t work. Practice is when something works, but you don’t know why.” This saying also captures something that mystified urology/radiation oncology teams for two decades. Androgen deprivation therapy (ADT) boosts the effectiveness of radiation therapy as a primary prostate cancer treatment. For 20 years, it worked in practice, but no one knew exactly why or how.

A remarkable paper out of three respected institutions (Memorial Sloan-Kettering Cancer Center, University of North Carolina/Chapel Hill, and Albert Einstein College of Medicine) delves deeply into the biochemistry of cellular and genomic processes to solve this stumper. “Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers” by Polkinghorn, et al.[i] offers an explanation based on thorough laboratory science.

Male hormones help prostate cancer cells

Prostate cancer cells thrive on androgens (male sex hormones), the most abundant of which are testosterone and dihydrotestosterone. The normal growth and function of the prostate gland depends upon androgens, and so do PCa cells. Androgens act as a sort of messenger, affecting the behavior of both healthy and cancerous prostate cells by binding to and activating androgen receptors (proteins) that are expressed in prostate and PCa cells. In turn, the androgen receptor “regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance…”[ii]

At the risk of oversimplifying, I explain it like this. Radiation is harmful to cells because it damages DNA, the core instruction manual for a living being to develop, survive and reproduce. The instructions are converted to messages for producing proteins, the molecules that work to keep our bodies functioning normally. If the DNA is damaged, the cell doesn’t work well, and ultimately can’t clone itself. Prostate cancer cells exposed to enough radiation eventually become incompetent, a process that requires sustained or repeated doses of radiation because the cells don’t die all at once. Cancer cells are more susceptible to radiation than healthy cells, but if healthy cells get enough radiation, they too will either mutate, die off, or both. If you are old enough to remember the Cold War, you probably had fear of radiation from nuclear weapons drilled into you—and this radiation effect is the reason why.

All cells are instructed to live until they are programmed to die (a natural process called apoptosis). All cells—including cancer cells—have built-in instructions for self-repair if exposed to a threat such as chemotherapy, ablation…and of course, radiation.

Since cancer cells are able to hijack the body’s healthy survival biochemical messengers for their own use, this is where androgens come in. In the presence of male hormones, androgen receptors are activated in a way that “switches on” a DNA repair gene that helps the PCa cell survive the effects of radiation exposure. So, in theory, depriving them of androgens weakens them. But how?

The Polkinghorn study provides answers

Androgen deprivation therapy (ADT) is a therapeutic, non-curative approach to controlling prostate cancer (PCa). It is most often prescribed for advanced or recurrent PCa when a local treatment is not appropriate or has failed; more recently it is also being seen as a “boost” for primary radiation therapy, and even in some cases a way to extend the duration of Active Surveillance.

ADT uses pharmaceutical drugs to block the systemic effects of androgens throughout the body, and of course, in PCa cells. There are three types of blockade that can be used alone or in combination:

1. Androgen receptor antagonists inhibit androgen binding to androgen receptors; drugs include flutamide, bicalutamide, apalutamide, or enzalutamide
2. LHRH agonists prevent the pituitary gland from producing the hormone needed for the testicles to produce androgens, thereby shutting off the flow; drugs include Lupron, Zoladex, etc.
3. CYP17 inhibitor prevents PCa cells themselves from making small amounts of androgens; currently the drug abiraterone (Zytiga) is used for this.

The Polkinghorn study involved many laboratory tests at the cellular and even genetic level. The research team experimented on PCa cells using various androgen and radiation doses to analyze their effect on cells’ androgen receptors and how they impact DNA. They explored the connection between increased PCa cell vulnerability to radiation and various points in the cancer cell’s life and cloning cycle. They observed that when androgens stimulate androgen receptor signaling, the PCa cells increased the expression of DNA repair genes (i.e. made more of them) which then accelerated the repair of radiation-caused cancer cell damage. Thus, by triggering androgen receptors, androgens helped cancer cells resist radiation. Ultimately, the authors demonstrated how depriving PCa of androgens causes more DNA damage to cancer cells while inhibiting their ability to clone themselves. In short, ADT makes radiation more effective.

The importance of this paper lies in providing the understanding of why and how ADT boosts the effectiveness of radiation therapy. However, the authors also note that given differences in individual patients and among prostate cancer cell lines, ADT has a general but not universal benefit. That said, the work of Polkinghorn and colleagues elucidates the synergistic effect between ADT and radiation. Theory and practice are finally in harmony.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE et al. Cancer Discov. 2013 November. 3(11);1245-53. [ii] Ibid.