L15 Androgen Receptor Pharmacology

the use of signal transduction inhibitors is important in the treatment of cancer, where

normal signal transduction can become hyper-activated

how is testosterone released

• the hypothalamus secretes Gonadotropin-releasing hormone which binds to the gonadotropin-releasing hormone receptor on the pituitary

• the pituitary secretes Leutinising hormone (LH) which binds to the LH receptor on the testes which causes the release of testosterone into the prostate

how does testosterone interact with the prostate

• testosterone enters the prostate as testosterone Salpha-reductase

• this forms DHT which binds to AR

• this releases HSP90 and AR-DHT complex forms a dimer with another AR-DHT complex which attaches to the AR target gene

• RNA polymerase binds to the AR target gene to initiate mRNA transcription and translation

• this forms prostate specific antigen (PSA) survival and proliferation proteins which then release PSA out of the prostate

describe the androgen receptor structure

• X chromosome has an Xp head (q11.2) and an Xq tail (q12)

• AR-FL gene at the 5’ end has an Exon 1, 2, 3, 4 and 5, 6, 7 and 8 at the 3’ end (UTR)

• AR-FL AF-1 is NTD Tau-1(142-485) and Tau 5(351-528) attached to a DBD. DBD attached to a hinge which is attached to an LBD (AF-2) (669-919)

ADT

androgen deprivation therapy

ADT reduces or interferes with androgens which

blocks receptor activation

androgen fuels the growth of

prostate cancer

Androgen deprivation therapy slows

growth of prostate cancer

• includes surgical and chemical castration

• first line treatment for metastatic PC

• improves survival

• significant side effects- dysfunction, fatigue, muscle loss, hot flushes, mood changes, increased risk of heart disease

give an example of an androgen receptor antagonist

Enzalutamide

what is the androgen receptor antagonist Enzalutamide mechanism of action

• competitively binds to the ligand binding domain of the androgen receptor preventing the binding of an androgen ligand

• inhibits translocation of the AR into the nucleus

• Prevents binding of the AR to DNA to inhibit transcription of AR target genes

castration resistant prostate cancer (CRPC)

despite response rates with GnRH and androgen receptor antagonists, within 18 months 90% of men develop treatment resistance

CRPC is

incurable

• AR remains active in resistant disease

• AR still remains a valid therapeutic target

inhibiting AR signalling at different parts of the

signalling circuit may prove therapeutically beneficial

describe the intratumoral and adrenal steroid hormone synthesis mechanism of CRPC

increased intratumoral androgens

describe the AG gene amplification mechanism of CRPC

• increased AR expression

• increased hypersensitivity to low T levels

describe the AR mutations, gain-of-function mechanism of CRPC

• point mutations T877A, W741C, F876L and T878A

• increased promiscuity, activation by AR inhibitors flutamide, bcalutamide, enzalutamide and progesterone

describe the AR splice variants mechanism of CRPC

• Truncated AR (AR-V7), LBD deficient

• constrictive active AR without ligand

describe the AR coregulators mechanism of CRPC

• Increased AR co-activators

• Decreased AR co-repressors

Describe the alternative signalling mechanism of CRPC

• upregulation of anti-apoptotic pathways such as AKT

• loss of tumour suppressor PTEN which inhibits AKT

up-regulation of the… is a mechanism of CRPC

glucocorticoid receptor (GR)

AR splice variant (AR-V7)

AR is constitutively active without the need for androgens

Characterisation of AR-V7 function in PC

• determined how AR-V7 is regulated

• pathways that AR-V7 regulates

• potential target therapies for AR-V7

what is the AR coregulator

KMT5A

what is KMT5A as the AR coregulator

• lysine methyltransferase: mono-methylates H4K20, and non-histone proteins

• KMT5A interacts with the AR and is required for AR transcription

• KMT5A regulates oncogenic pathways such as CDC20 in CRPC

IKBKE activity enhances AR levels through

modulating the Hippocampus pathway

how is the hippocampus pathway targeted in PC

• activation of the hippo pathway switches off cell growth transcription

• a cascade of kinase signalling leads to phosphorylation and proteasome-mediated degradation of downstream effector, YAP (txf)

• YAP associates with the AR

• YAP stabilisation causes upregulation of YAP-target genes including c-Myc

• Higher levels of c-Myc up-regulates transcription of c-Myc target genes such as AR

• IKBKE leads to YAP stabilisation, and ultimately increases AR signalling

• IKBKE and YAP are often over expressed in PC

what is adrogenetic alopecia (AGA)

• male pattern hair loss (MPHL)

• excessive follicular sensitivity to androgens

• causes shrinkage of hair follicules, replacing terminal hairs with vellus hairs

what is treatment for adrogenetic alopecia (AGA)

Finasteride which is a 5-alpha-reductase inhibitor

how does finasteride work for adrogenetic alopecia (AGA)

blocks the conversion of testosterone to its active form dihydrotestosterone (DHT) lowering DHT levels

future directions for prostate cancer treatments

• new combinations of existing treatments- PARP inhibitors and ADT, IKBKE inhibitor and ADT

• targeted radiation therapy- combined with PARP inhibitors