Androgen receptor

Approximately 110 kD nuclear transcription factor with a central DNA binding domain, a ligand binding domain and both ligand dependent and independent transcriptional activation domains.

Androgen receptor is a member of the nuclear steroid hormone receptor family.

Androgen receptor functions as a DNA binding transcription factor.

Androgen receptor has 4 functional domains: M-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain.

N-terminal domain is the primary effector area and reset is responsible for the major transactivation function of androgen receptor.

Androgen receptor resides in the cytoplasm and is stabilized by heat shock proteins.

Upon binding to the androgen ligand binding it undergoes confirmational change and is translocated to the nucleus initiating transcription activity.

AR pathway is the main driver of disease after prostate cancer develops castration resistance.

Drugs targeting the androgen receptor such as abiratone, enzalutamide, apalutamide, and darolutamide show benefit in Patients  with castrate resistant prostate cancer, support the hypothesis that androgen receptors remain active and represent an important mechanism driving prostate cancer growth, even at low levels of testosterone.

AR direct therapies by suppression of androgen synthesis or through blockade of AR have become the main therapeutic strategies for hormonal resistant prostate cancer.

Traditional secondary hormonal manipulations include antiandrogens, corticosteroids, ketocanazole, and estrogen.

Prostate cancer depends on androgen receptor activity but it not responsible for transformation to malignant cells, but can do so when exposed to unknown nonautonomous dependent oncogenes.

Prostate cancer cells must regulate and degrade the androgen receptor if they are to proliferate.

In a low testosterone environment of androgen deprivation therapy, prostate cancer cells adapt to produce far more androgen receptor, allowing them to capture every possible molecule of testosterone.

Androgen receptors mutate so they function even in the absence of testosterone.

Prostate cancer initially is highly responsive to androgen deprivation therapy but over time becomes resistant and continues to grow.

Regulates transcription of genes involved in cell proliferation, differentiation and apoptosis.

Activation occurs in many cases of castration resistant prostate cancer and may be secondary to gene amplification.

Most patients with prostate cancer respond to androgen deprivation therapy, but they invariably relapse, and develop castration resistant prostate cancer.

In castrate resistant prostate cancer androgen receptor activity is driven by intratumoral synthesis of testosterone and dihydrotestosterone from precursor steroids synthesized by the adrenal glands, and to a lesser extent by tumor cells from cholesterol.

Synthesis of precursor steroids can be markedly suppressed by the treatment with an inhibitor of enzyme CYP17A1, such as abiraterone a standard second line hormonal therapy for metastatic castrate resistant prostate cancer.

The AR pathway is persistently activated in most cases of castration resistant disease with maintenance of tissue androgen concentration using adrenal androgen precursors or through intratumoral androgen synthesis.

Prostate cancer that is progressive in the setting of low circulating levels of testosterone most lesions are still sensitive to androgen receptor signaling.

Androgen receptor signaling remains active even when castrate levels of less than 50 ng/dL of serum testosterone are present.

AR axis remains functional in advanced prostate cancer by several mechanism, including mutation, overexpression, and ligand independent activation.

Approximately one third of patients with hormone refractory prostate cancer have androgen receptor gene amplification.

Androgen receptor inhibitors include enzalutamide, apalutamide, and daralutamide.

A subset of patients treated with androgen receptor inhibitors will develop mutations in the receptor gene that can be activated by androgens, estrogens and progesterones.

Androgen receptor variant 7 (AR-V7) is an RNA mutation of the AR seen in patients with long-term hormonal therapy usually who have received AR-targeted therapies.

The AR-V7 variant is a truncated receptor and does not have a hormone binding domain so that standard hormone therapies are unlikely to be beneficial.

AR-V7 is associated with poor survival.

Antagonists-include flutamide, bicalutamide, and nilutamide can be used alone or in combination with castration to bloc androgen effects.

Enzalutamide can suppress androgen receptor activity by more potent direct competitive antagonists of androgen binding to the androgen receptor

Enzalutamide and abiraterone associated with improved survival in castration resistant prostate cancer.

Enzalutamide and other second generation androgen receptor antagonist more effectively impair androgen receptor binding to chromatin and are more potent antagonists.

One way that castrate resistant prostate cancer maintains androgen recptor signaling is by overexpressing cytochrome P450c17 (CYP17), a key enzyme in extragonadal androgen biosnthesis and includes the adrenal gland, prostate and intratumoral regions.

Abiraterone, is a CYP17 inhibitor and when used with prednisone compared to placebo plus prednisone in men with metastatic castration resistant prostate cancer who had disease progression after docetaxel chemotherapy: was associated with a 35% reduction in the risk of death, with a median survival of 14.8 months versus 10.9 months among patients who received placebo plus prednisone.

Abiraterone resulted in an improved prostate specific antigen response, and improved objective response on the bases of radiographic findings, longer time to disease progression, and a longer progression free survival on the basis of radiographic findings.

Approximately half the patients with castrate resistant prostate cancer respond to abiraterone and enzalutamide, but most relapse within 1-2 years.

Leave a Reply

Your email address will not be published. Required fields are marked *