Prostate cancer Flashcards
What is the main ‘zone/area’ of the prostate gland?
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.
What is the prostate gland, and its importance?
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)
Describe prostate enlargement.
(What is it also known as)
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.
How can prostate cancer be diagnosed?
Prostate specific antigen (PSA) blood test
Prostate examination (digital rectal examination)
MRI, ultrasound and biopsies
What does the PSA test indicate?
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
State the main subtypes of prostate cancer.
Acinar adenocarcinoma
Ductal adenocarcinoma
What is Acinar adenocarcinoma?
Develops in gland cells that line the prostate gland.
(Acinus cells are grape shaped ducts)
What is Ductal adenocarcinoma?
Starts in cells that line the ducts of prostate gland.
Ductal adenocarcinoma spreads quicker than acinar
What is the most common type of prostate cancer?
Acinar adenocarcinoma
Where are the most common sites of prostate cancer metastasis?
Pelvic lymph nodes
Bladder
Bone matastasis (pelvic and spinal cord)
State the key genetic alterations involved in prostate cancer (disease progression).
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
List the different prostate cancer statuses.
Localised prostate cancer
Castrate-specific prostate cancer (CSPC)
Castrate-resistant prostate cancer (CRPC)
Hormone-refractory prostate cancer (HRPC)
What is Localised prostate cancer
Cancer completely localised inside the prostate (hasn’t spread).
This can be curative.
What is Castrate-sensitive prostate cancer (CSPC)
Cancer controlled by keeping testosterone level as low as if testicles were removed (castrate-level).
(chemical castration; blocking levels of testosterone)
What is Castrate-resistant prostate cancer (CRPC)
Cancer growing even when testosterone levels are at or below castrate level.
What is Hormone-refractory prostate cancer (HRPC)
Cancer no longer helped by any type of hormone therapy.
Synonymous with androgen-independent or castrate-resistant.
List forms of non-pharmaceutical treatments for prostate cancer.
Active surveillance: PSA, DRE, imaging/biopsies
Radiotherapy
Radical prostacetomy
Pelvic lymph node dissection
Where does Acinar adenocarcinoma develop
Develops in gland cells that line the prostate gland.
Prostate Cancer Genetics: Key Molecular Alterations
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.
describe hormone therapies for prostate cancer
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.
LHRH agonists MOA and example
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
LHRH antagonists MOA and example
Prevents LHRH from receptor binding in the pituitary gland.
= reduced LH secretion = prevents androgen production be the testicles
Degarelix
When are LHRH agonists and antagonists not effective
not effective for CRPC and HRPC
Compare and contrast LHRH agonists and LHRH antagonists
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.
What is the purpose of androgen deprivation therapies?
To reduce androgens.
Androgens stimulate prostate cancer cells to grow
Androgen synthesis inhibitors
MOA and example
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
When is an Androgen synthesis inhibitor useful
in CRPC
Androgen receptor antagonist
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
What is the limitation of Androgen receptor antagonist
They do not prevent androgen production so are used in combination with androgen deprivation therapy (LHRH therapies)
What are Taxanes
Taxanes are mitotic inhibitors that stabilise microtubule assembly
Chemotherapies for prostate cancer.
MOA and example
Taxanes stop the expression of the androgen receptor or downregulate pro-apoptotic proteins (e.g.BAX protein).
docetaxel, cabazitaxel
what is the role of PARP
PARP (poly(ADP)-ribose polymerase) are enzymes involved in damaged DNA repair.
PARP inhibitors
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
Example of a PARP inhibitor
Olaparib
When are PARP inhibitors effective?
PARP inhibitors are primarily used to treat cancers with deficiencies in homologous recombination repair, such as those with BRCA1/2 mutations.
When are immunotherapies used in prostate cancer
used in advanced castrate-resistant prostate cancer
List examples of immunotherapies
Pembrolizumab
Sipuleucel-T (Provenge)
Pembrolizumab
checkpoint inhibitor (anti-PD-1 antibody)
Targets PD-1 on T-cells.
Inhibits PD-1/PD-L1 binding (= T-cell activation)
Sipuleucel-T (Provenge)
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.’
side effects of Sipuleucel-T (Provenge)
Side effects: Nausea, joint aches, fever, headache
How does Provenge work?
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
Compare and contrast different treatment approaches for prostate cancer
*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).
