Targeted Therapies

Question 1

What are the basic subclasses of antineoplastic drugs?

Answer 1

• alkylating agents
• antimetabolites
• plant alkaloids
• hormones and antagonists
• targeted therapy

Question 2

What do antimetabolites do?

Answer 2

Attach groups to DNA

Question 3

What do plant alkaloids do?

Answer 3

Stabilise or destabilise microtubules

Question 4

What are examples of alkylating agents?

Answer 4

• cyclophosphamide
• melphalan
• chlorambucil

Question 5

What are examples of antimetabolites?

Answer 5

methotrexate

Question 6

What are examples of plant alkaloids?

Answer 6

• taxanes

- vinca alkaloids

Question 7

What are examples of hormones and antagonists?

Answer 7

• anti-oestrogens

- anti-androgens

Question 8

What are examples of targeted therapy?

Answer 8

• monoclonal antibodies

- small tyrosine kinase inhibitors

Question 9

What are the cancer targets?

Answer 9

• BEST = found in cancer cells but not normal cells
• NEXT BEST = more targets in cancer cells than normal
• targets in both, normal cell regenerates

Question 10

Why is genomic profiling important?

Answer 10

• can identify prognostic markers
• identify if drugs will be effective
• whether patients develop resistance
• patients develop adverse effects

Question 11

Why are targeted therapies necessary?

Answer 11

• more precise treatment
• interfere with specific molecules stopping growth and progression
• oral therapies used in combination with adjuvant therapies

Question 12

How does tyrosine kinase receptor signalling work?

Answer 12

• ligand binds to EC domain
• dimerization of tyrosine kinases causing conformational change in the IC domain (phosphorylation)
• tyrosine phosphorylated = recruit adaptor proteins
• triggers cascade of signalling pathways
• MAPK/PI3 kinase pathway activated
• increase in growth survival and motility of cells

Question 13

What does antibody therapy consist of?

Answer 13

• antibody inhibitors of growth receptors preventing growth signal
• antibody drug conjugates targeting drug to tumour cells

Question 14

What are the 3 mechanisms of monoclonal antibodies?

Answer 14

• kill tumour cells directly
• kill tumour cells via an immune-mediated mechanism
• vascular or stromal ablation

Question 15

How do monoclonal antibodies directly kill tumour cells?

Answer 15

• block signals
• induce apoptosis
• deliver toxic payload

Question 16

How do monoclonal antibodies kill tumour cells via an immune mediated mechanism?

Answer 16

• induce phagocytosis
• complement dependent cytotoxicity
• antibody dependent cell cytotoxicity

Question 17

How do monoclonal antibodies allow vascular or stromal ablation?

Answer 17

• possible delivery of toxic payload

- VEGF antagonism

Question 18

What does cetuximab do?

Answer 18

• cetuximab

Binds to extracellular part of RTK and prevents dimerization preventing signalling

Question 19

Which monoclonal antibodies target EGFR?

Answer 19

Cetuximab

Panitumumab

Question 20

Which monoclonal antibodies target HER2/ERB2?

Answer 20

Trastuzumab

Question 21

Which monoclonal antibodies target HER3?

Answer 21

Pertuzumab

Question 22

Which monoclonal antibodies target VEGFR?

Answer 22

Bevacizumab

Question 23

How does trastuzumab Herceptin prevent cleavage?

Answer 23

prevents cleavage of HER2 receptor

• if HER2 overexpressed = mutations
• allows EC parts to be cleaved off
• therefore continuously activated

Question 24

What are the 4 actions of trastuzumab Herceptin?

Answer 24

1) Prevents cleavage
2) Inhibits dimerization
3) antibody dependent cell-mediated cytotoxicity
4) activate endocytosis of the HER2 receptors

Question 25

What is the role of VEGF?

Answer 25

- formation of new blood vessels - upregulated antigen in cancer - protects endothelial cells from death by activating PKC pathways/upregulating Bcl2 - activity mediated by VEGFR1 and 2 - indirectly functions as survival for tumour cells

Question 26

What is the mechanism of action of bevacizumab?

Answer 26

- blocks receptor | - inhibits tumour growth and metastasis

Question 27

What is the significance of the last syllable of monoclonal antibodies?

Answer 27

- U and ZU humanised (panitumumab and trastuzumab) | - XI chimeric (rituximab)

Question 28

What is the significance of the previous syllable of the monoclonal antibodies?

Answer 28

``` tu(m) = general tumour ma(r) = breast pro(o) = prostate co(l) = colon ci(r) = circulatory ```

Question 29

How do antibodies access normal tissue?

Answer 29

Blood vessels have intact endothelial layer

Question 30

How do antibodies access tumour tissue?

Answer 30

- leak blood vessels so all sized molecules access malignant tissue - no lymphatic drainage system so macromolecules retained - enhanced vascular permeability of circulating antibodies = accumulation in solid tumours

Question 31

What are conjugated antibodies?

Answer 31

- cytotoxic drug attached via Fc part link | - antibody binds to cancer cell and cytotoxic load is adjacent

Question 32

What is an example of a conjugated antibody?

Answer 32

trastuzumab emtansine (kadcycla) - for HER2+ women but inoperable breast cancer - effective but expensive

Question 33

How do naked antibodies work?

Answer 33

- activate immune system - target immune system checkpoints - inhibit activity of antigen and prevent growth

Question 34

What are the 2 types of tyrosine kinase inhibitors?

Answer 34

TKIs of growth factors | Inhibition of other kinases

Question 35

What is the kinase domain?

Answer 35

- binding pocket for ATP to cause phosphorylation | - if pocket blocked = phosphorylation blocked

Question 36

What is an example of a TKI?

Answer 36

Tarceva | - non-small cell lung cancer

Question 37

What are small molecule TKIs?

Answer 37

- target oncogene product (EGFR) - inhibit signalling at key steps - safer than chemo - specific side effects - specificity

Question 38

What do TKIs end in?

Answer 38

tinib

Question 39

What are examples of mutation cancers?

Answer 39

Adenocarcinoma PIK3CA mutations KRAS

Question 40

What is the significance of drug resistance in tyrosine kinase domain of EGFR in lung cancer?

Answer 40

- exon 20 mutations | - to gefitinib or erlotinib

Question 41

What are examples of first generation EGFR TKIs?

Answer 41

(reversible) - erlotinib - geitinib

Question 42

What are examples of second generation EGFR TKIs?

Answer 42

(irreversible) | - afatinib

Question 43

What are examples of third generation TKIs?

Answer 43

(mutant-selective) | - osimertinib

Question 44

What are some side effects of targeted therapy?

Answer 44

- skin changes - hypertension (VEGF) - slow wound healing and blood clotting (EGFR) - congestive heart failure (HER2)

Question 45

What skin changes are cause by targeted therapy>

Answer 45

- skin rashes (EGFR) - dry skin - itchy skin - hand foot syndrome (VEGF) - changes in hair (alopecia/brittle) - dry/red eyes/red or tender eyelids

Question 46

How does trastuzumab cause cardiotoxicity?

Answer 46

HER2 survival pathways in the heart are inhibited = increase in NO = endothelial cell dysfunction