Androgen Receptor Pharmacology Notes
Androgen Receptor Pharmacology
Introduction
Androgen Receptor (AR) signal transduction plays a critical role in prostate cancer.
Signal transduction inhibitors are important for treating diseases like cancer, where normal signal transduction can become hyper-activated.
Androgen Receptor Signaling Pathway
The hypothalamus releases Gonadotropin-Releasing Hormone (GnRH).
GnRH acts on the pituitary gland via the Gonadotropin-releasing hormone Receptor.
The pituitary gland releases Luteinizing Hormone (LH).
LH acts on the testes via the Luteinizing hormone receptor to produce testosterone.
Testosterone can be converted to Dihydrotestosterone (DHT) by 5alpha-Reductase.
In the prostate, testosterone and DHT bind to the Androgen Receptor (AR).
HSP90 is involved in the process.
AR, DHT, RNA Polymerase, and other factors lead to transcription of AR target genes.
AR target genes regulate the production of:
Prostate Specific Antigen (PSA)
Survival Proteins
Proliferation Proteins
Androgen Receptor Structure
The AR-FL gene is located on the X chromosome.
The AR-FL protein contains several key domains:
NTD (N-terminal domain): Includes AF-1 and TAU-1.
DBD (DNA-binding domain).
Hinge region.
LBD (Ligand-binding domain): Includes AF-2.
Relevant Exons: 1, 2, 3, 4, 5, 6, 7, 8
NTD spans from amino acid 1 to 537, containing TAU-1 (142-485), and AF-1 (1-351).
DBD spans from amino acid 537 to 626.
Hinge region spans from amino acid 626 to 669.
LBD spans from amino acid 669 to 919, containing AF-2 (912-919).
Historical Context: Dr. Charles Huggins
Dr. Charles Huggins discovered (1940s and 50s) that removing the testicles (orchiectomy) to eliminate testosterone caused regression in prostate cancer (PC).
Androgen Deprivation Therapy (ADT)
ADT reduces or interferes with androgens, blocking receptor activation.
Androgens fuel PC growth, so ADT slows it down.
Includes surgical and chemical castration.
First-line treatment for metastatic PC.
Improves outcome and survival.
Associated with significant side effects.
Androgen Receptor Antagonist: Enzalutamide
Mechanism of action:
Competitively binds to the ligand-binding domain (LBD) of the Androgen Receptor, preventing DHT binding.
Inhibits translocation of the AR into the nucleus.
Prevents binding of AR to DNA, inhibiting transcription of AR target genes.
ADT Side Effects
Erectile dysfunction
Mood changes
Hot flushes
Memory problems
Bone loss
Brain fog
Fatigue
Sleep disruption
Increased risk of heart disease
Castration Resistant Prostate Cancer (CRPC)
Despite initial response to GnRH and AR antagonists, 90% of men develop treatment resistance within 18 months.
AR remains active in resistant disease, making it a valid therapeutic target.
Inhibiting AR signaling at different parts of the signaling circuit may be beneficial.
Mechanisms of CRPC
Intratumoral & adrenal steroid hormone synthesis:
Increased intratumoral androgens.
AR gene amplification:
Increased AR expression.
Increased hypersensitivity to low T levels.
AR mutations, gain-of-function:
Point mutations such as T877A, W741C, F876L, T878A.
Increased promiscuity, activation by AR inhibitors like flutamide, bicalutamide, enzalutamide, and progesterone, respectively.
AR splice variants:
Truncated AR (AR-V7), LBD deficient.
Constitutively active AR without ligand.
AR coregulators:
Increased AR co-activators.
Decreased AR co-repressors.
Alternative signalling:
Upregulation of anti-apoptotic pathways such as AKT.
Loss of tumor suppressor PTEN, which inhibits AKT.
Up-regulation of the glucocorticoid receptor (GR)
AR-V7 in CRPC
AR splice variant (AR-V7).
AR is constitutively active without the need for androgens.
Enzalutamide and other AR antagonists that target the AR LBD are ineffective in inhibiting AR-V7 because the antagonist cannot bind to AR-V7 as the LBD is deficient.
Characterisation of AR-V7 Function in PC
Research from Newcastle University has significantly contributed to characterising the function of AR-V7.
Focus areas include:
How AR-V7 is regulated.
Pathways that AR-V7 regulates.
Potential therapeutic targets in CRPC.
AR Coregulator – KMT5A
KMT5A is a lysine methyltransferase that mono-methylates H4K20 and non-histone proteins.
KMT5A interacts with the AR and is required for AR transcriptional activity.
KMT5A regulates oncogenic pathways such as CDC20 in CRPC.
Targeting the Hippo Pathway in PC
Research from Newcastle University focuses on this.
Demonstrated that IKBKE activity enhances AR levels through modulating the Hippo Pathway.
The Hippo Pathway
Activation of the Hippo pathway switches off transcriptional programmes that promote cell growth.
Involves a cascade of kinase signaling leading to phosphorylation and proteasome-mediated degradation of downstream effector, YAP, which is a transcription factor.
YAP associates with the AR.
YAP stabilization causes upregulation of YAP-target genes including c-Myc.
Higher levels of c-Myc, in turn, up-regulate transcription of c-Myc target genes such as AR.
IKBKE leads to YAP stabilization and ultimately increased AR signaling.
IKBKE and YAP are often overexpressed in many cancers, including PC.
Androgenetic Alopecia (AGA)
Also known as male pattern hair loss (MPHL).
Caused by excessive follicular sensitivity to androgens.
Results in shrinkage of hair follicles, replacing terminal hairs with vellus hairs.
Treatment involves Finasteride, a 5-alpha-reductase inhibitor.
Finasteride blocks the conversion of testosterone to its active form, dihydrotestosterone (DHT), lowering DHT levels.
Future Directions
New Prostate Cancer Treatments
New combinations of existing treatments:
PARP inhibitors and ADT
IKBKE inhibitor and ADT
Targeted radiation therapy combined with PARP inhibitors
Conclusions
Improved understanding of mechanisms causing CRPC.
AR signalling remains key in driving PC progression.
AR signalling could be targeted with novel agents.
Utilisation of combination therapies.
Androgen Receptor Pharmacology
Introduction
Androgen Receptor (AR) signal transduction plays a critical role in prostate cancer initiation, progression, and treatment resistance. Dysregulation of AR signaling can lead to uncontrolled cell growth and proliferation.
Signal transduction inhibitors are important for treating diseases like cancer, where normal signal transduction can become hyper-activated, leading to disease progression.
Androgen Receptor Signaling Pathway
The hypothalamus releases Gonadotropin-Releasing Hormone (GnRH).
GnRH acts on the pituitary gland via the Gonadotropin-releasing hormone Receptor, stimulating the release of gonadotropins.
The pituitary gland releases Luteinizing Hormone (LH).
LH acts on the testes via the Luteinizing hormone receptor to produce testosterone, the primary androgen in males.
Testosterone can be converted to Dihydrotestosterone (DHT) by 5alpha-Reductase, an enzyme present in various tissues, including the prostate.
In the prostate, testosterone and DHT bind to the Androgen Receptor (AR), a nuclear receptor protein.
HSP90 is involved in the process, acting as a chaperone protein to stabilize the AR complex.
AR, DHT, RNA Polymerase, and other factors lead to transcription of AR target genes, influencing gene expression.
AR target genes regulate the production of:
Prostate Specific Antigen (PSA), a biomarker used to monitor prostate cancer progression.
Survival Proteins, which promote cell survival and inhibit apoptosis.
Proliferation Proteins, which stimulate cell division and growth.
Androgen Receptor Structure
The AR-FL gene is located on the X chromosome.
The AR-FL protein contains several key domains:
NTD (N-terminal domain): Includes AF-1 and TAU-1, involved in transcriptional activation.
DBD (DNA-binding domain): Responsible for binding to specific DNA sequences.
Hinge region: Flexible region that allows for conformational changes in the AR.
LBD (Ligand-binding domain): Binds to androgens like testosterone and DHT, includes AF-2.
Relevant Exons: 1, 2, 3, 4, 5, 6, 7, 8
NTD spans from amino acid 1 to 537, containing TAU-1 (142-485), and AF-1 (1-351).
DBD spans from amino acid 537 to 626.
Hinge region spans from amino acid 626 to 669.
LBD spans from amino acid 669 to 919, containing AF-2 (912-919).
Historical Context: Dr. Charles Huggins
Dr. Charles Huggins discovered (1940s and 50s) that removing the testicles (orchiectomy) to eliminate testosterone caused regression in prostate cancer (PC), demonstrating the androgen dependence of prostate cancer.
Androgen Deprivation Therapy (ADT)
ADT reduces or interferes with androgens, blocking receptor activation and downstream signaling.
Androgens fuel PC growth, so ADT slows it down by depriving cancer cells of their hormonal fuel.
Includes surgical and chemical castration, both aimed at lowering androgen levels.
First-line treatment for metastatic PC, improving patient outcomes.
Improves outcome and survival rates in many cases.
Associated with significant side effects, impacting the quality of life.
Androgen Receptor Antagonist: Enzalutamide
Mechanism of action:
Competitively binds to the ligand-binding domain (LBD) of the Androgen Receptor, preventing DHT binding, thus inhibiting receptor activation.
Inhibits translocation of the AR into the nucleus, preventing its interaction with DNA.
Prevents binding of AR to DNA, inhibiting transcription of AR target genes, resulting in reduced expression of pro-cancer proteins.
ADT Side Effects
Erectile dysfunction
Mood changes
Hot flushes
Memory problems
Bone loss
Brain fog
Fatigue
Sleep disruption
Increased risk of heart disease
Castration Resistant Prostate Cancer (CRPC)
Despite initial response to GnRH and AR antagonists, 90% of men develop treatment resistance within 18 months, presenting a clinical challenge.
AR remains active in resistant disease, making it a valid therapeutic target for further interventions.
Inhibiting AR signaling at different parts of the signaling circuit may be beneficial in overcoming resistance.
Mechanisms of CRPC
Intratumoral & adrenal steroid hormone synthesis:
Increased intratumoral androgens, allowing cancer cells to produce their own fuel.
AR gene amplification:
Increased AR expression, leading to increased receptor numbers.
Increased hypersensitivity to low T levels, making cancer cells more responsive to minimal androgen stimulation.
AR mutations, gain-of-function:
Point mutations such as T877A, W741C, F876L, T878A, altering receptor function.
Increased promiscuity, activation by AR inhibitors like flutamide, bicalutamide, enzalutamide, and progesterone, respectively, making AR less specific.
AR splice variants:
Truncated AR (AR-V7), LBD deficient, resulting in constitutively active AR.
Constitutively active AR without ligand, bypassing the need for androgen binding.
AR coregulators:
Increased AR co-activators, enhancing AR transcriptional activity.
Decreased AR co-repressors, reducing the inhibition of AR signaling.
Alternative signalling:
Upregulation of anti-apoptotic pathways such as AKT, promoting cell survival.
Loss of tumor suppressor PTEN, which inhibits AKT, leading to increased AKT signaling.
Up-regulation of the glucocorticoid receptor (GR): GR can compensate for AR signaling in some cases.
AR-V7 in CRPC
AR splice variant (AR-V7), lacking the ligand-binding domain.
AR is constitutively active without the need for androgens, driving cancer progression.
Enzalutamide and other AR antagonists that target the AR LBD are ineffective in inhibiting AR-V7 because the antagonist cannot bind to AR-V7 as the LBD is deficient, underscoring the need for alternative therapeutic strategies.
Characterisation of AR-V7 Function in PC
Research from Newcastle University has significantly contributed to characterising the function of AR-V7, providing insights into its role in CRPC.
Focus areas include:
How AR-V7 is regulated, identifying potential regulatory mechanisms.
Pathways that AR-V7 regulates, determining its downstream effects.
Potential therapeutic targets in CRPC, aiming to develop new treatments.
AR Coregulator – KMT5A
KMT5A is a lysine methyltransferase that mono-methylates H4K20 and non-histone proteins, influencing gene expression.
KMT5A interacts with the AR and is required for AR transcriptional activity, modulating AR function.
KMT5A regulates oncogenic pathways such as CDC20 in CRPC, impacting cell cycle progression.
Targeting the Hippo Pathway in PC
Research from Newcastle University focuses on this, exploring innovative approaches.
Demonstrated that IKBKE activity enhances AR levels through modulating the Hippo Pathway, impacting AR signaling.
The Hippo Pathway
Activation of the Hippo pathway switches off transcriptional programmes that promote cell growth, acting as a tumor suppressor.
Involves a cascade of kinase signaling leading to phosphorylation and proteasome-mediated degradation of downstream effector, YAP, which is a transcription factor, regulating gene expression.
YAP associates with the AR, modulating AR activity.
YAP stabilization causes upregulation of YAP-target genes including c-Myc, impacting cell proliferation.
Higher levels of c-Myc, in turn, up-regulate transcription of c-Myc target genes such as AR, creating a positive feedback loop.
IKBKE leads to YAP stabilization and ultimately increased AR signaling, influencing AR-driven cancer progression.
IKBKE and YAP are often overexpressed in many cancers, including PC, suggesting their role in tumorigenesis.
Androgenetic Alopecia (AGA)
Also known as male pattern hair loss (MPHL).
Caused by excessive follicular sensitivity to androgens, leading to hair loss.
Results in shrinkage of hair follicles, replacing terminal hairs with vellus hairs, altering hair structure.
Treatment involves Finasteride, a 5-alpha-reductase inhibitor, which is a common therapeutic approach.
Finasteride blocks the conversion of testosterone to its active form, dihydrotestosterone (DHT), lowering DHT levels, reducing androgen effects on hair follicles.
Future Directions
New Prostate Cancer Treatments, aiming for more effective therapies.
New combinations of existing treatments:
PARP inhibitors and ADT, exploring synergistic effects.
IKBKE inhibitor and ADT, targeting alternative pathways.
Targeted radiation therapy combined with PARP inhibitors, improving local control.
Conclusions
Improved understanding of mechanisms causing CRPC, enhancing therapeutic strategies.
AR signalling remains key in driving PC progression, making it a central target.
AR signalling could be targeted with novel agents, developing innovative therapies.
Utilisation of combination therapies, improving patient outcomes.