MD5 - Anti-androgens

Risk of prostate cancer

1 in 8 men will get prostate cancer

Risk increases with age

Typically > 50 and most common age is 65-69

Risk factors of prostate cancer

Family history

• Father/ brother who has been diagnosed with prostate cancer previously means you’re 2.5x more likely to develop it

• If mother/sister has had breast cancer

Ethnicity

• black men risk is 1 in 4

Age

• over 50

PSA

Prostate Specific Antigen

a specific protein made by the prostate, some of which enters the bloodstream and can be measured via a blood test.

An enlarged, inflamed or infected prostate can cause elevated PSA

Elevated PSA may also indicate cancer in the prostate (but may be other things)

Stages of Prostate Cancer: (T)NM

T1 – tumour is contained in the prostate, too small to be felt by digital rectal examination (DRE) or seen on a scan (may be diagnosed after elevated PSA then biopsy)

T2 – tumour still contained in the prostate but can be felt by DRE or seen on a scan

Divided in to:

• T2a –tumour is only in half of 1 of the 2 lobes of the prostate

• T2b – it is in more than half of 1 lobe

• T2c – it is in both lobes

T3 – tumour has spread through the capsule surrounding the prostate and may be in nearby tissues

• T3a – spread through the capsule

• T3b – spread to the seminal vesicles that produce fluid for semen

T4 – spread into areas close by such as the bladder, rectum or the muscle that controls urination

Stages of Prostate Cancer: T(N)M

N0 – means there is no cancer in the lymph nodes near the prostate

N1 - means there is cancer in 1 or more lymph nodes close by

Stages of Prostate Cancer: TN(M)

M0 – means the cancer has not spread to another part of the body (hence locally advanced prostate cancer is ALWAYS M0)

M1 – means the cancer has spread to another part of the body

So advanced prostate cancer is ALWAYS M1

Numbered staging of Prostate Cancer

Stage 1 – Tumour contained in the prostate

Stage 2 – Tumour is bigger but still contained in the prostate

Stage 3 – Tumour has started to break out of the outer capsule and may be in the seminal vesicles

Stage 4 – Tumour has spread outside the prostate – maybe local, such as the bladder, but may be further, e.g. to bones

Gleason Scale

based on taking a biopsy of the prostate and looking at the morphology of the cells

Androgen Independence

prostate cancer always starts out needing the testosterone when it no longer needs the testosterone signal it is androgen independent (very bad)

How does Prostate cancer develop from prostatic epithelium?

Options for treatment of prostate cancer

• watchful waiting - mainly for frail older men with slow-growing tumours

• active surveillance - small tumours confined to prostate

• surgery - frequently used but major side effets

• hormone therapy - ONLY for hormone dependent tumours

• chemotherapy - for hormone independent/relapsed cancer

• high-intensity focused ultrasound - energy into prostate cancer to “de-bulk” aka break it up

• External beam radiotherapy - for small tumours confined to the prostate

• Permanent seed brachytherapy - permanent source of radiation which is implanted into the tumour itself and will damage it because it’s sat inside the tumour

How does testosterone promote proliferation?

• binds to androgen receptor (with hydrophobic interactions) outside cell

• causes a conformation change

• AR+T complez translocates to the cell’s nucleus where it signals for proliferation

First gen AR inhibitors

flutamide - originally antibacterial and then used for anti-androgen activity - - hepatotoxic so little use in prostate cancer atm

• Possible due to mitochondrial toxicity

nilutamide - made from flutamide and a little less hepatotoxic

• selective antagonist

bicalutamide - binding mode is known and this drug is widely used

• Often used with gonadotropin releasing hormone (GnRH) or castration

Common structural components of 1st generation anti-androgens

• CF₃

• aromatic ring

• amide bond

2nd generation anti-androgens

Enzalutamide

• good in vivo efficacy

• good PK

• high steady state brain tissue level - rare cns toxicity

Apalutamide

• good in vivo efficacy

• good PK

• low steady state brain tissue level (good)

Darolutamide

• short t_1/2

When is Apalutamide used?

non metastatic castrate resistant prostate cancer

Bicalutamide MOA

binds to AR (via H-bonds) but doesn’t cause conformational change

acts as competititve inhibitor

bicalutamide complex is internalised but cannot be translocated to the nucleus

some agonist activity especially at mutant AR

How does bicalutamide bind to AR?

binds using nitrile of the bicalutamide and forms a H-bond with the amine of the Arg 752

No Thr877 binding

on the other end of it’s molecule it has another with Asn705 and forms a hydrogen bond at the hydroxyl group of the bicaludamine with the carboxyl of the Asn705

How does Testosterone bind to AR?

it forms a H-bond with the receptor at the carboxyl group and binds with the amine of the Arg 752 (part of the binding site)

On the other end it also picks up a Thr877 at the hydroxyl group

Mechanism of resistance to enzulatamide

primary/acquired resistance is usually developed from cancer reccurance and progression

but the other methods of resistance are:

• AR signalling pathways are altered - typically AR gene amplification which increases the no. of AR so not all blocked by drug

• AR mutation - converts drug from antagonist to agonist

• AR (splice) variant - typically after castration but role in resistance is not very clear

• Metabolic changes - increased androgen synthesis to overwhelm the inhibition as it is only competitive

• lineage plasticity - cell line becomes AR independent via epigenetic changes so testosterone is no longer needed

How much does enzalutamide extend life by?

4-5 months for castrate resistant metastatic prostate cancer

Biosynthesis of testosterone

Cholesterol

Pregnenolone → progesterone

either make Androtenediol (pregnenolone) or Androstenedione (progesterone) which can both be converted into testosterone

CYP17A1

exists as tetramer therefore 4 binding sites

it is an oxidising enzyme (has an iron in the centre of it)

converts progesterone to 17a hydroxyprogesterone (intermediate before androtenedione)

Drugs that inhibit CYP17A1

Need something that is a ligand for metals - has a lp and will bind to the iron e.g.

• Ketoconazole (non-specific inhibitor of CYPs)

• Abiraterone - selective inhibitor of CYP17A1

• Abiraterone acetate - prodrug of abiraterone

How does progesterone bind to CYP17A1?

C=O forms a h-bond to the Asn202 of CYP17A1

hydrocarbon part sticks to the hydrophobic side-chain

How does abiraterone bind to CYP17A1?

OH forms a h-bond to the Asn 202