Systemic Anti cancer treatment

Question 1

What is chemotherapy?

Answer 1

• COMPOUND TARGETING DNA, RNA & PROTEINS - AIM IS TO FORCE CELLS INTO APOPTOSIS! - IT IS NON -SPECIFIC TO CANCER CELLS
  *ALL RAPIDLY DIVIDING CELLS ARE AFFECTED *

Question 2

How is chemotherapy delivered?

Answer 2

• IV & ORAL PREPARATIONS
• FREQUENCY OF ADMINISTRATION= CYCLES
• CYCLES DETERMINED BY PHARMACOKINETICS
• COMBINATION CHEMO - increased EFFICACY
• NEOADJUVANT (given before surgery)/ ADJUVANT (reduce risk of cancer returning)/ DISEASE CONTROL
  PALLIATIVE(control disease for as long as possible)

Question 3

What are the 3 main types of chemotherapy?

Answer 3

• Alkylating agents and platinum drugs - form DNA adducts
  blocking DNA replication (all phases of cell cycle)
  certain alkylating agents have ability to create cross links (changing structure of the DNA helix) and can act in all phases of cell cycle
• Antimetabolites - structurally mimic essential molecules
  required for cell division (S phase of cell cycle)
  These may be incorporated into new nuclear material or bind irreversibly with vital enzymes for cell division
• Organic drugs - vinca alkaloids / taxanes / anthracyclines

Question 4

Give examples of organic drugs?

Answer 4

• Vinca alkaloids - bind to tubulin and prevent
  microtubule assembly - which is essential for metaphase and mitosis
• Taxanes - bins to beta tubulin subunit inhibiting
  depolymerisation and disrupting mitotic spindle
• Anthracyclines - microbial antibiotic targets
  topoisomerase II (enzyme that releases torsional stress during the DNA replication)

Question 5

Side effects of chemotherapy?

Answer 5

nausea and vomiting

Question 6

Give examples of personalised systemic therapies?

Answer 6

• Hormonal Therapies - Anti - oestrogen, Aromatase
  inhibitors
• Targeted Therapies - EGFR, VEGF, CDK 4/6
• Immunotherapy - PD 1, PD -L1, CTLA - 4

Question 7

Which hormones are linked to breast cancer?

Answer 7

Oestrogens (estradiol/esterone) play major role

Oestrogens promote cell proliferation within the breast tissue (higher rate of
cell division = more chances for mutations)

Prolonged exposure to oestrogen- increased RISK

Question 8

What are breast cancer drugs?

Answer 8

Breast cancer drugs
Anti- oestrogen = Tamoxifen: Binds to the
oestrogen receptor and blocking oestrogen induced proliferation of cells

Aromatase inhibitors = Letrozole: Block
conversion to androgens to oestrogen

Question 9

Describe how EGF works?

Answer 9

EGF binds to the tyrosine kinase receptor on cell membrane and this leads to receptor dimerization and autophosphorylation.
Following this there is activation of intracellular transducers including RAS pathway and transcription.

Question 10

What have tyrosine kinase inhibitors been developed for?

Answer 10

to target tumours that express the EGF receptor

Question 11

What stem cells is the immune system derived from?

Answer 11

haematopoietic stem cells

Question 12

What do B cells do?

Answer 12

produce tumour specific antibodies- induce cell lysis and ultimately death

Question 13

What do T cells do?

Answer 13

helper T cell vs cytotoxic t cells - kill cells

Question 14

What are immune checkpoints for?

Answer 14

to ensure that self tolerance is maintained

Question 15

What are immune checkpoints activated by?

Answer 15

Activated by receptor ligand
binding (PD-1 to PD-L1)
(CTLA-4 to B7)

Question 16

What do immune checkpoint inhibitors do?

Answer 16

(PD1 PDL1 AND CTLA-4)
removal of the brakes of the
immune system allowing
increased T cell activity

Question 17

What are cyclic kinases and cyclin dependent kinases responsible for?

Answer 17

movement of cells through cell cycle

Question 18

What does cyclin D along with CDK4/6 responsible for?

Answer 18

helps to move cells from the G0 resting phase into G1 to begin growth

production of cyclin d regulates cyclin e - which controls passage into s phase

Question 19

Immunotherapy side effects?

Answer 19

• Colitis - most common - 30% develop diarrhoea of any grade and
  10% have severe grade 3-4 in dual IO.10
• Pneumonitis - more common in PD-L1 treatment reference 11
• Hypophysitis/ Thyroid dysfunction/ Diabetes - 5-10% develop
  endocrine adverse events reference 12
• Hepatitis - occurs <5% 11
• Dermatitis - most frequent toxicity for PD-L1 and CTLA-4 11
• Nephritis - <1 % 11
• Neurological <0.2% 11

Question 20

What are side effects of EGF receptor inhibitors?

Answer 20

not entirely specific and still cause disruption to normal cells.
Resulting in side effects such as diarrhoea, dry skin, rash , hypertension and deranged liver function.

Question 21

What does the inhibitor ,palbociclib, do?

Answer 21

block the progression of cells through cell cycle in metastatic breast cancer

Question 22

What are the descendents of stem cells called?

Answer 22

progenitor cells

Question 23

What are progenitor cells divided into?

Answer 23

myeloid or lymphoid

Question 24

Which cells respond early?

Answer 24

neutrophils and NK cells

Question 25

What cells respond later?

Answer 25

B and T cells -adaptive immune response

Question 26

How do PD-1 inhibitors drive killing of cancer cells by t cells?

Answer 26

PD-1 found on T cells binds to another protein called PD-L1 helping to keep T cells from killing other cells including cancer cells.
PD-1 inhibitors block binding to PD-L1 and this means the brakes on immune system are released and t cells can kill cancer cells.

Question 27

What is pembrolizumab? (KEYTRUDA)

Answer 27

selective humanised IgG4 monoclonal antibody targeted at the PD-1 checkpoint

blocks PD-1 receptors from binding to immune dampening PD-1 and PD-2 ligands in the tumour