Emmanuel S. Antonarakis, MBBCh
The last decade has witnessed a leap forward in the treatment of the challenging castration-resistant form of prostate cancer (CRPC), following the discovery that targeting the androgen receptor (AR) remains a viable strategy in this advanced form of disease. In spite of this, CRPC remains incurable, with most patients developing resistance to currently available AR-targeting therapies.
With increased understanding of the biology of CRPC and the mechanisms of action of AR-targeting drugs, researchers are developing a growing appreciation for the extensive heterogeneity and complexity of both prostate cancer and androgen signaling.
Androgen Receptor Targeting and Resistance
This figure illustrates the complexities of androgen receptor signaling in prostate cancer and some of the agents used to target activity.
3βHSD1 indicates 3β-hydroxysteroid dehydrogenase type 1; AR, androgen receptor; C, C terminal of DBD; CYP17, cytochrome P450 17; DBD, DNA binding domain; DHEA, dihydroepiandrosterone; DHT, dihydrosterone; GR, glucocorticoid receptor; N, N terminal of DBD; PSA, prostate-specific antigen; T, testosterone.
Adapted from Stein MN, Patel N, Bershadskiy A, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014;16(3):387-400.
By applying clinical trial experience with AR-targeting agents, the field is attempting to stay one step ahead of this resilient foe by trying new combinations and developing new drugs to overcome resistance while searching for biomarkers to help guide treatment decision making (Table 1)
Understanding of AR Signaling Evolves
Table 1. Novel Agents to Overcome AR Resistance in Active Clinical Trials
*Trial is ongoing, but not recruiting participants.
AR indicates androgen receptor; CRPC, castration-resistant prostate cancer; CYP17A, cytochrome P450 17A enzyme; mCRCP, metastatic castration-resistant prostate cancer.
In recent years, comprehensive genomic profiling studies have pinned down four major signaling pathways involved in the development and progression of prostate cancer, but more than 70 years ago the Nobel Prize-winning findings of Charles B. Huggins and colleagues had already intimately linked one of these pathways to prostate cancer.
That was the pathway regulated by the androgen receptor, a member of the nuclear steroid hormone family that acts as a DNA-binding transcription factor and plays a major role in normal prostate function. Residing in an inactive form in the cytoplasm, ARs move into the nucleus upon binding of androgens and stimulate transcription of genes involved in cell cycle regulation, growth, and survival. In prostate cancer, increased levels of circulating androgens promote AR signaling and aberrant activation of these cellular processes.
The importance of the AR pathway in prostate cancer has driven the clinical development of therapies designed to reduce the levels of androgens or to block the AR signaling network. This began with androgen deprivation therapy (ADT), primarily achieved through surgical intervention or chemical castration (agonists and antagonists of gonadotropin-releasing hormone, which regulates testosterone synthesis). Neither surgical nor chemical castration is completely effective at reducing circulating androgen levels, and patients inevitably progress to more aggressive and ultimately fatal CRPC, in which the cancer continues to grow despite the low androgen environment. Researchers turned to targeting the AR to block the body’s ability to use androgens, to complement the use of ADT, and to induce maximal androgen blockade. The first generation of AR antagonists were highly effective, but eventually developed agonist activity, especially in the presence of high levels of AR, and were ineffective in CRPC.CRPC: A Major Therapeutic Challenge
Originally, CRPC was believed to have evolved to become androgen-independent, driving unresponsiveness to ADT and antiandrogens and limiting their utility in CRPC.
During the past decade, a significant paradigm shift has occurred following revelations of the continued critical role of the AR in CRPC progression.