Past papers

Question 1

How does ipillimumab function in malignant melanoma treatment?

Answer 1

It blocks the interaction between CTLA-4 and its ligands CD80 and CD86.

Normally CTLA-4 functions to dampen down immune response pathways of T-cell activation and thus blocking this leads to potentiating anti-tumour response.

(CTLA-4 normally helps prevent autoimmunity developing)

Can be given to MM patients where their melanoma is not suitable for removal and has metastasied or after prior therapy has failed.

Very expensive drug - £25,000 for 1 dose, requires 4 doses in total.

Question 2

Vemurafenib and dabrafenib are two new ____ agents for MM.

Answer 2

Oral tyrosine kinase inhibitor - BRAF inhibitor.
BRAF is a gene that is mutated in 60% of melanomas to become constitutively active -> cell proliferation and tumour growth.

Only suitable in patients with BRAF v600 mutation.

Question 3

Vemurafenib and dabrafenib are two new oral tyrosine kinase inhibitors for use in MM patients with what mutation?

Answer 3

BRAF v600 mutation.

BRAF is a gene that is mutated in 60% of melanomas and becomes constitutively active -> cell proliferation and tumour growth.

Vemurafenib can lead to increased skin sensitivity - patients need to wear SPF 30-50 in all weathers and wear long sleeved clothing. Also tinted windows at home and on car.

Question 4

Which oral tyrosine kinase inhibitor for use in MM patients with the BRAF v600 mutation can cause increased skin sensitivity?

Answer 4

Vemurafenib can lead to increased skin sensitivity - patients need to wear SPF 30-50 in all weathers and wear long sleeved clothing. Also tinted windows at home and on car.

Drug interactions via CYP450 enzymes: warfarin and oestrogens.

Question 5

What are the main differences and similarities between Vemurafenib and Dabrefenib?

Answer 5

Similar because:
MM treatment in people with BRAF v600 mutation.
Similar efficacy.
Block the tyrosine kinase.
Both can cause cutaneous squamus cell carcinoma

Different:
Vemurafenib causes increased skin sensitivity and has a 20% risk of cutaneous squamous cell carcinoma.

Dabrafenib is taken twice daily on empty stomach.
Dabrafenib has a 10% risk of cutaneous squamous carcinoma but its side effects tend to be better tolerated.

Question 6

Which has a higher reported incidence of cutaneous sqaumous cell carcinoma: Vemurafenib or Dabrafenib?

Answer 6

Vem: 20%
Dab: 10%

Patients on either should be advised to be aware of any new skin lesions/changes in skin. Any new lesions can normally be removed easily with surgery.

Question 7

What is pembrolizumab?

Answer 7

An anti-PD-1 humanised monoclonal antibody which blocks the interaction between PD-1 and PD-L1/PD-L2 its ligands. This releases the inhibition of the immune response - takes off the breaks.

First line in MM patients with no BRAF v600 mutation as slightly cheaper/more tolerable than ipillimumab.

Was fast-tracked through the Early Access to Medicines scheme (EAMS).

Risks of fast-tracking include missed side effects that take a long time to become apparent.

Question 8

How does Pembrolizimumab work?

Answer 8

It inhibits the interaction between the immune system dampening PD1 receptor and its ligands PD-L1/PD-L2.

This takes the breaks off the immune system. Allows the T cells to do their cytotoxic thing on the cancer cells.

Question 9

How do androgen blocking drugs such as _________ and __________ prevent tumour flare? What is tumour flare?

Answer 9

Bicalutamide and cytoperone compete with DHT (active testosterone metabolite) at the receptor level within prostate cancer cells.

Because LHRH agonist occupies the receptors of the pituitary glad, and for th first seven to ten days after prostate cancer hormone therapy begins, the levels of testosterone spike.

It takes a while for them to become desensitised.

Tumour flare can cause a temp increase in tumour volume and symptoms.

Question 10

What are the two new oral therapies for metastatic prostate cancer?

Answer 10

Abiraterone and Enzalutamide

Question 11

What is the mechanism of action of enzalutamide in the treatment of metastatic prostate cancer?

Answer 11

Blocks interaction of androgens to androgen receptors.

Blocks the translocation of any bound androgen-androgen receptor complexes to the nucleus.

Blocks the association of any activated androgen receptors that have managed to be translocated with DNA.

Question 12

What is the method of action abiraterone?

Answer 12

Inhibits androgen production from the testes, adrenal gland and prostate tumour cells.

It must be given with a steroid as it is an inhibitor of CYP 17A1. This enzyme is responsible for both cortisol and androgen production.

The side effects of abiraterone are due to low cortisol levels and include peripheral oedema, hypertension, oedma and increased risk of UTI (unknown why).

Question 13

What are the side effects of chemotherapy with docetaxel and prednisolone?

Answer 13

Bone marrow suppression: neutropenia,
Severe alopecia (not really an issue as treating elderly men),
N/V
Myalgia
Fluid retention- premed with dexamethasome.

Question 14

What pre-medication is needed with docetaxel and prednisolone chemotherapy of metastatic disease?

Answer 14

Dexamethasome 3 days prior.

Also need to make sure patient has anti-emetics prescribed.

Question 15

FBC results in order for chemo with docetaxel and prednisolone to go ahead

Answer 15

platelets >100

neuts >1.5

Question 16

Why has ipillimumab changed the prognosis for MM?

Answer 16

IT is the first agent to show an increase in survival in MM. The previous agent Dacarbazine for 30 years had not been shown to have a significant effect on survival rates.

Question 17

Why was pembrolizumab fast tracked?

Answer 17

VIA EAMS.
BAsed on data from KEYNOTE-001, largest phase 1b study of an anti-PD-1 therapy in patients with advanced melanoma.

Overall response was 24%, response duration lasted from 1.4 to 8.5 months.

Question 18

Goserelin and triptorelin are what?

Answer 18

LHRH analogues given monthly/3monthly SC depot injections.

Disrupt the normal pulsatile release of LHRH. Initially this leads to an increase in LH release followed by a decrease in LH and testosterone.

The inital rise in LH can cause a transient increase in tumour volume = tumour flare.

Treated with androgen blocking drugs like bicalutamine and cyproterone.

Question 19

What are 3 characteristics that make stem cells likely candidates for the origin of cancer?

Answer 19

1. Expression of telomerases
2. Proto-oncogenic pathways
3. Niche environments to support the growth of metastases

Question 20

Why is the expression of telomerases by stem cells a characteristic supporting the CSC hypothesis?

Answer 20

The ends of chromosomes contain tandem repeats known as telomeres. DNA polymerase cannot copy right to the end of the chromosomes, telomeres shorten by 100-200 bases with each round of DNA replication.

When telomeres get too short, they are recognised as damaged DNA and p53 is activated to induce apoptosis.

As such, most cells have a finite number of divisions they can possibly undergo.

Telomerases are RT enzymes containing an RNA template to add TTAGGG repeats to chromosome ends. They are only found in some rapidly dividing cells and germline cells.

Stem cells also express telomerases making them “immortal”.

Telomerases are also expressed by cancer cells, meaning cancerous mutations are preserved, and more mutations are added over time.

The unlimited replicative potential of cancer cells is one of the hallmarks of cancer (Hanrahan and Weinberg, 2000 and 2011), and telomerase expression is indiciative of poor prognosis.

An explanation of how cancer cells express telomerases can be that they originate from stem cells. (with unlimited replicative potential via telomerases, stem cells are more likely to pick up multiple cancerous mutations than mature cells).