Prostate cancer

Question 1

What is the main ‘zone/area’ of the prostate gland?

Answer 1

The peripheral zone
It makes up >70% of prostate glandular tissue.
It has the largest contribution to normal prostate function.

The peripheral zone is the most common site of origin for 80% of prostate tumours.

Question 2

What is the prostate gland, and its importance?

Answer 2

The prostate gland secretes fluid that nourishes and protects sperm.
The vasa deferential brings sperm from the testes to the seminal vesicles.
During ejaculation, the prostate squeezes fluid into the urethra. (Expelled with sperm as semen)

Question 3

Describe prostate enlargement.
(What is it also known as)

Answer 3

Benign prostatic hyperplasia (BPH)

BPH is more common as men get older.
It can block urine flow out of the bladder.
This can lead to bladder, urinary tract or kidney problems.

Question 4

How can prostate cancer be diagnosed?

Answer 4

Prostate specific antigen (PSA) blood test
Prostate examination (digital rectal examination)
MRI, ultrasound and biopsies

Question 5

What does the PSA test indicate?

Answer 5

The prostate gland releases PSA molecules.
Low levels of PSA are normal.
High levels of PSA can be a sign of prostate cancer.
However, factors such as UTIs, vigorous exercise, certain medications or prostate stimulation can raise PSA levels

Question 6

State the main subtypes of prostate cancer.

Answer 6

Acinar adenocarcinoma
Ductal adenocarcinoma

Question 7

What is Acinar adenocarcinoma?

Answer 7

Develops in gland cells that line the prostate gland.
(Acinus cells are grape shaped ducts)

Question 8

What is Ductal adenocarcinoma?

Answer 8

Starts in cells that line the ducts of prostate gland.
Ductal adenocarcinoma spreads quicker than acinar

Question 9

What is the most common type of prostate cancer?

Answer 9

Acinar adenocarcinoma

Question 10

Where are the most common sites of prostate cancer metastasis?

Answer 10

Pelvic lymph nodes
Bladder
Bone matastasis (pelvic and spinal cord)

Question 11

State the key genetic alterations involved in prostate cancer (disease progression).

Answer 11

Fusions of ETS genes

Amplification of MYC oncogene

Deletion/Mutation of PTEN and TP53 tumour suppressor genes

During metastasis:
Amplification/mutation of Androgen receptor (AR) and BRCA

Question 12

List the different prostate cancer statuses.

Answer 12

Localised prostate cancer

Castrate-specific prostate cancer (CSPC)

Castrate-resistant prostate cancer (CRPC)

Hormone-refractory prostate cancer (HRPC)

Question 13

What is Localised prostate cancer

Answer 13

Cancer completely localised inside the prostate (hasn’t spread).
This can be curative.

Question 14

What is Castrate-sensitive prostate cancer (CSPC)

Answer 14

Cancer controlled by keeping testosterone level as low as if testicles were removed (castrate-level).
(chemical castration; blocking levels of testosterone)

Question 15

What is Castrate-resistant prostate cancer (CRPC)

Answer 15

Cancer growing even when testosterone levels are at or below castrate level.

Question 16

What is Hormone-refractory prostate cancer (HRPC)

Answer 16

Cancer no longer helped by any type of hormone therapy.
Synonymous with androgen-independent or castrate-resistant.

Question 17

List forms of non-pharmaceutical treatments for prostate cancer.

Answer 17

Active surveillance: PSA, DRE, imaging/biopsies

Radiotherapy

Radical prostacetomy

Pelvic lymph node dissection

Question 18

Where does Acinar adenocarcinoma develop

Answer 18

Develops in gland cells that line the prostate gland.

Question 19

Prostate Cancer Genetics: Key Molecular Alterations

Answer 19

Fusions of ETS genes. (erythroblast transformation specific family of transcription factors)
This fusion results in the overexpression of the (ERG) oncogene, promoting tumorigenesis by enhancing cell proliferation and invasion.

Amplification of MYC oncogene.
= increased expression of the MYC protein drives cell growth and proliferation.
MYC amplification is associated with aggressive prostate cancer and poor prognosis. It contributes to tumour progression and the development of castration-resistant prostate cancer (CRPC)

Deletion/mutation of PTEN and TP53 tumour suppressor genes.
Loss of PTEN leads to uncontrolled activation of the PI3K/AKT pathway, promoting cancer growth and survival.
Loss of p53 function allows for the survival and proliferation of cells with damaged DNA.

Amplification/mutation of AR and BRCA. (androgen receptor)
leads to increased AR protein levels, enhancing the sensitivity of cancer cells to low androgen levels
BRCA mutations are linked to more aggressive forms of prostate cancer and a higher likelihood of developing metastatic disease.

Question 20

describe hormone therapies for prostate cancer

Answer 20

Androgen Deprivation Therapy (ADT):

LHRH Agonists and Antagonists: LHRH agonists (e.g., leuprolide, goserelin) initially increase testosterone levels before downregulating receptors and reducing testosterone production. LHRH antagonists (e.g., degarelix) lower testosterone levels directly without the initial surge.

Enzalutamide block androgen receptors on prostate cancer cells, preventing testosterone from binding and stimulating cancer growth.

Androgen Synthesis Inhibitors:

Example: Abiraterone acetate inhibits CYP17, an enzyme critical for androgen production in the adrenal glands and prostate tumor tissue.
Mechanism: Reduces androgen levels beyond what is achieved by LHRH agonists or antagonists alone.

Question 21

LHRH agonists MOA and example

Answer 21

It initially stimulates the pituitary gland to release LH. the continuous administration leads to downregulation/desensitisation of LHRH receptor in the pituitary gland. This leads to a significant decrease in LH and testosterone

Goserelin

Question 22

LHRH antagonists MOA and example

Answer 22

Prevents LHRH from receptor binding in the pituitary gland.
= reduced LH secretion = prevents androgen production be the testicles

Degarelix

Question 23

When are LHRH agonists and antagonists not effective

Answer 23

not effective for CRPC and HRPC

Question 24

Compare and contrast LHRH agonists and LHRH antagonists

Answer 24

Onset of Action: LHRH antagonists reduce hormone levels more quickly and without the initial surge in hormone levels associated with LHRH agonists. This makes antagonists particularly useful when rapid testosterone suppression is needed, such as in cases of spinal cord compression due to metastatic prostate cancer.

Both classes share similar long-term side effects related to low hormone levels, but antagonists avoid the initial flare response.
Administration: LHRH agonists often require depot injections administered every few months, whereas some antagonists (like relugolix) offer an oral administration route.

Question 25

What is the purpose of androgen deprivation therapies?

Answer 25

To reduce androgens.

Androgens stimulate prostate cancer cells to grow

Question 26

Androgen synthesis inhibitors

MOA and example

Answer 26

target the enzymatic pathway involved in the production of androgens. Reducing levels in the body.

Abiraterone:
inhibits CYP17 which is expressed in prostatic tumour tissue and is required for androgen biosynthesis. = lowers androgen levels

Question 27

When is an Androgen synthesis inhibitor useful

Answer 27

in CRPC

Question 28

Androgen receptor antagonist

Answer 28

block androgen from binding to the androgen receptor.
prevent the nuclear translocation of the AR.
= inhibiting the transcription of genes that promote cancer cell growth

e.g. Enzalutamide and apalutamide

Question 29

What is the limitation of Androgen receptor antagonist

Answer 29

They do not prevent androgen production so are used in combination with androgen deprivation therapy (LHRH therapies)

Question 30

What are Taxanes

Answer 30

Taxanes are mitotic inhibitors that stabilise microtubule assembly

Question 31

Chemotherapies for prostate cancer.
MOA and example

Answer 31

Taxanes stop the expression of the androgen receptor or downregulate pro-apoptotic proteins (e.g.BAX protein).

docetaxel, cabazitaxel

Question 32

what is the role of PARP

Answer 32

PARP (poly(ADP)-ribose polymerase) are enzymes involved in damaged DNA repair.

Question 33

PARP inhibitors

Answer 33

PARP inhibitors bind to the PARP enzyme and inhibit its activity, preventing the repair of single-strand DNA breaks. This leads to the accumulation of double-strand breaks during DNA replication, causing cell death, especially in cells deficient in homologous recombination repair (e.g., BRCA1/2 mutations).

if BRCA is normal it will fix the double break by homologous recombination

Question 34

Example of a PARP inhibitor

Answer 34

Olaparib

Question 35

When are PARP inhibitors effective?

Answer 35

PARP inhibitors are primarily used to treat cancers with deficiencies in homologous recombination repair, such as those with BRCA1/2 mutations.

Question 36

When are immunotherapies used in prostate cancer

Answer 36

used in advanced castrate-resistant prostate cancer

Question 37

List examples of immunotherapies

Answer 37

Pembrolizumab
Sipuleucel-T (Provenge)

Question 38

Pembrolizumab

Answer 38

checkpoint inhibitor (anti-PD-1 antibody)

Targets PD-1 on T-cells.
Inhibits PD-1/PD-L1 binding (= T-cell activation)

Question 39

Sipuleucel-T (Provenge)

Answer 39

induces an immune response targeted against Prostatic acid phosphate (PAP).

‘Patient-derived immune cells, including antigen-presenting cells, are exposed ex vivo to a fusion protein (PA2024), linking prostatic acid phosphatase (PAP) with granulocyte-macrophage colony-stimulating factor (GM-CSF). After reinfusion into the patient, the activated immune cells educate T cells about the presence of PAP in prostate cancer cells.’

Question 40

side effects of Sipuleucel-T (Provenge)

Answer 40

Side effects: Nausea, joint aches, fever, headache

Question 41

How does Provenge work?

Answer 41

Activated Antigen-presenting cells in provenge present prostatic acid phosphate (PAP) peptides to T cells

T cells recognise prostatic acid phosphate (PAP) peptides as evidence of cancer and become activated

activated T cells recognise PAP peptides on the surface of cancer cells and attack

Question 42

Compare and contrast different treatment approaches for prostate cancer

Answer 42

*LHRH agonists and antagonists are not effective when prostate cancer is castrate resistant or hormone-refractory
*Androgen receptor antagonists do not prevent androgen production, so used in combination with Androgen deprivation therapy (ADT).