Closing in on a ‘Smarter’ Androgen Deprivation Therapy

By Hannelore V. Heemers, PhD

Hannelore V. Heemers, PhD

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the United States. Patients who present with localized disease and for whom deferral of treatment is not recommended are treated with surgery or radiation therapy with curative intent.

Some men, however, present with prostate cancer that has spread beyond the confines of the prostate. In others, prostate cancer recurs after prostatectomy or radiation therapy. Men with advanced prostate cancer are given androgen deprivation therapy that targets the action of the androgen receptor.

The androgen receptor is a ligand-dependent transcription factor. Currently, androgen deprivation therapy (ADT) prevents androgen receptor signaling by reducing the availability of its ligand or the ability of the androgen receptor to interact with and be activated by its ligand.

Overall, these forms of ADT are initially effective in inducing remission. However, the extent and duration of remission is variable among patients, and eventually the cancer recurs during ADT. Strikingly, in the vast majority of cases, prostate cancer that recurs under the selective pressure of ADT remains dependent on the androgen receptor for growth.

As with other targeted therapies, the manner in which prostate cancer cells bypass the blocks that have been imposed on the androgen receptor signaling axis often involves adaptations that lead to gain of function for the androgen receptor. With few exceptions, failure of ADT is responsible for the approximately 30,000 American prostate cancer deaths per year.

Identifying other targeting strategies

Figure 1. Targeting androgen receptor (AR) transcriptional output to develop selective forms of androgen deprivation therapy (ADT). Current ADT prevents production of dihydrotestosterone (DHT), the most bioactive androgen, or interferes with the interaction between ARs and DHT. Selective ADT exploits therapeutically distinct AR-dependent cellular processes (cell migration, DNA damage response, etc.) that are associated with prostate cancer progression. From: Elbanna M, Heemers HV. Alternative approaches to prevent androgen action in prostate cancer: Are we there yet? Discov Med. 2014 May;17(95):267-274. Used with permission from Discovery Medicine. ARE = androgen response element

We propose that other tactics to target androgen receptor action for prostate cancer treatment should be pursued. It is apparent that the most important part of the androgen receptor signaling axis — namely its transcriptional output, which ultimately controls prostate cancer cell behavior and fate — has not yet been considered for therapeutic intervention.

The transcription function of the androgen receptor and the molecular determinants that control its activity are increasingly evident. During the last decade, systems biology approaches have identified the spectrum of androgen-responsive genes and genomewide androgen receptor binding sites in prostate cancer cells, and gene expression profiling and next-generation sequencing have been performed on clinical prostate cancer specimens obtained at different stages of disease progression.

Gaining androgen receptor insights

Collectively, the data and insights from these studies are enabling the preliminary systemic characterization of regulation of the androgen-dependent transcriptome in prostate cancer model systems and the validation of its relevance to clinical situations, specifically the progression of prostate cancer to its lethal stage.

These “big data” projects provide for the first time an incredible opportunity to start isolating androgen receptor action that drives prostate cancer to the lethal stage, and can provide an entirely novel target for therapy.

Increasingly, the androgen receptor is appreciated for its ability to control distinct cellular functions differentially at the molecular level. Conceptually, this gain in knowledge allows us to determine the fraction(s) of androgen action that is most important to prostate cancer progression and to exploit the underlying regulatory mechanisms for therapeutic intervention.

Such an approach could be used to develop forms of androgen ablation that are more selective than current ADT, which may be viewed as “oversized,” i.e., targeting all androgen receptor action, when it may be sufficient to prevent only the fraction that conveys aggressive prostate cancer behavior.

Focusing on selective control

The feasibility of a novel selective form of ADT that interferes with a select fraction(s) of androgen action that drives prostate cancer progression is supported by a body of research. For instance, we have identified fractions of androgen receptor action that selectively control cell migration or lipid synthesis, both of which are features that underlie prostate cancer progression. Insights into the molecular basis for androgen regulation of these biological processes are leading to the implementation of druggable targets for prostate cancer therapy.

While a one-size form of androgen deprivation therapy may fit all, the tighter fit provided by such treatment options may be more effective and comfortable for the patient.

Dr. Heemers is an associate staff member of the Department of Cancer Biology in Cleveland Clinic’s Lerner Research Institute.