Targeted Therapy

Question 1

What are the benefits of targeted therapies?

Answer 1

ID within an individual all the mutations in the cancer they have, then use this information to:

• Improved diagnosis
• Reducing serious side effects
• Reducing use ineffective drugs
• Improving patient survival
• Improving quality of life
• Reduce costs

Question 2

What are the best therapeutic targets for cancer cells? [1]

What is the next best target? [1]

Answer 2

Best therapeutic targets are found in cancer cells but not in normal cells e.g. gene product from a translocation

When there are more targets in cancer cells than normal cells (e.g. gene amplification: overexpression of HER2 or EGFR)

Question 4

Name a drug that targets EGRF mutation [2]

Answer 4

Gefitinib or erlotinib

Question 5

Tyrosine kinase receptors:

Name 4 key antibody targets that are GF receptors and / ligands

Answer 5

Epidermal growth factor receptor (EGFR)

HER2 (no ligand)

HER2/3 (ligand: HER2 can bind to HER3 – activates different pathway)

Vascular endothelial growth factor (VEGF)

Question 6

Name two key intracellular growth pathways [2]

Answer 6

MAPK and PI3Kinase

Question 7

State the results of switching of receptor / kinase activity of t

MAPK kinase

Answer 7

MAPK Pathway:

• Less proliferation

PI3Kinase:
* Less cell growth
* Less proliferation
* Less angiogenesis

Question 8

raS

Question 9

State the two main approaches for targeted therapies [2]

Answer 9

Antibodies
Small molecules tyrosine kinase inhibitors

Question 10

State difference in antibody and small molecule kinase inhibitors

Answer 10

Antibodies:
* high selectivity
* targets are often restricted to the cell surface
* require intravenous or subcutaneous dosing because of their large molecular weight
* Can be conjugated to cytoxic drugs

Small molecule kinase inhibitors:
* vary in selectivity
* Oral
* Bind- ATP binding sites
* Can potentially bind a wider range of extracellular and intracellular targets (> one kinase)

Question 11

Describe the mechanism of antibodies [2] and SMKI [1]

Answer 11

Antibody:
* Produce antibodies that target extracellular part of tyrosine kinase receptor
* Inhibits ligand binding or causes the ligand to bind in an area that doesn’t cause dimerization

SMKI:
* Binds to ATP binding pocket & intracellular-P cant occur

Question 12

State the overall three mechanisms of monoclonal antibodies [3]

Answer 12

Killing tumour cell directly

Killing tumour cells via an immune-mediated mechanism

Vascular or stromal ablation: VEGF antagonsim

Question 13

Monoclonal antibodies and cancer therapy mechanisms:

Explain how killing tumour cells directly via monoclonal antibodies works [4]

Answer 13

• Inhibit ligand binding
• Or possible delivery of toxic payload
• Signalling blocked
• Apoptosis induced

Question 14

Monoclonal antibodies and cancer therapy mechanisms:

Explain how killing tumour cells directly via an immune-mediated mechanism works [3]

Answer 14

• Induction of phagocytosis
• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cell cytotoxicity (ADCC)

Question 15

Monoclonal antibodies and cancer therapy mechanisms:

Explain how killing tumour cells directly via vascular or stromal ablation works [1]

Answer 15

VEGF antagonism

Question 16

Cetuximab inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Answer 16

Cetuximab inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Question 17

Trastuzumab (Aka Herceptin) inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Answer 17

Trastuzumab (Aka Herceptin) inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Question 18

Pertuzumab inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Answer 18

Pertuzumab inhibits which receptor:

HER2
HER2/HER3
EGFR
VEGF

Question 19

What are the two components of Trastuzumab emtansine (Kadcycla)? [2]

Answer 19

Herceptin (acts as the transporter)
AND
Anti-microtubule agent: DM1

Question 20

Describe mechansim of trastuzumab emtansine (Kadcycla)?

Answer 20

Kadycycla is formed from the conjugate binding of Herceptin with DM1, which is an anti-microtubule agent

Drug is taken up by lysosome.

Within the lysosome: herceptin and DM1 dissociate and are released into cell

DM1 attacks cell tubule

Question 21

What is the difference in mechanisms between Herceptin (Trastuzumab) alonve versus Trastuzumab emtansine (Kadcycla)

Answer 21

Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor

Trastuzumab emtansine undergoes receptor-mediated internalization (herceptin acts as the transporter) into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death

Question 22

What is first line treatment of HER2-positive breast cancer? [3]

Answer 22

Pertuzumab (HER2/HER3 blocker), in combination with trastuzumab (HER2 blocker) and docetaxel

Question 23

What is second line treatment of HER2-positive breast cancer? [2]

Answer 23

Trastuzumab - emtansine (Kadcycla)

Question 24

What is third line treatment of HER2-positive breast cancer? [2]

Answer 24

Trastuzumab-deruxtecan

Question 25

Describe overall mechanism of Small Molecule Tyrosine Kinase Inhibitors (e.g. Tarceva)

Answer 25

Tarceva has similar structure to ATP Binds to **ATP binding pocket in the cell membrane** causes competitive inhibition in ATP binding pocket-inhibit function of kinases

Question 26

How does HER2 resistance occur?

Answer 26

As tumours develop they acquire mutations. With HER2: **becomes truncated**: extracellular part becomes truncated. As a result, **kinase activity is switched off** (doesn’t need receptor activation to switch on intracellular pathway). As a result Herceptin stops working as there is no binding sit

Question 27

Explain what a second generation tyrosine kinase inhibitor is [1] Name a second gen tyrosine kinase inhibitor for EGFR in NSCLC [1]

Answer 27

Drug for the new mutation of the tyrosine kinase receptor Mutations associated with drug resistance to erlotinib so **Osimertinib** prescribed (fits the new ATP binding site)

Question 28

Which cascade is perhaps the most important oncogenic driver of human cancers? PI3 Kinase MAP Kinase KRAS AKT

Answer 28

Which cascade is perhaps the most important oncogenic driver of human cancers? PI3 Kinase **MAP Kinase** KRAS AKT

Question 29

Which drug prevents the HER2/HER3 dimer from forming? Trastuzumab Pertuzumab Cetuximab Kadcycla

Answer 29

Which drug prevents the HER2/HER3 dimer from forming? Trastuzumab **Pertuzumab** Cetuximab Kadcycla

Question 30

Which drug stops HER2 binding to another HER2 Trastuzumab Pertuzumab Cetuximab Kadcycla

Answer 30

Which drug stops HER2 binding to another HER2 **Trastuzumab** Pertuzumab Cetuximab Kadcycla

Question 31

Name a small molecule tyrosine kinase Inhibitors [1]

Answer 31

**Tarceva** (Erlotinib)

Question 32

Tarceva (Erlotinib) targets which of the following HER2 HER2/HER3 EGFR VEGF

Answer 32

Tarceva (Erlotinib) targets which of the following HER2 HER2/HER3 **EGFR** - used in small cell lung cancer VEGF

Question 33

Name three drug targers for kinase inhibitors [3]

Answer 33

* Transcription * Receptor tyrosine kinase signalling * Proto oncogenes

Question 34

Name a AE of targeting VEGF [1] and EGFR [1]

Answer 34

**VEGF**: High blood pressure **EGFR**: Slow wound healing and blood clotting

Question 35

This rash comes from which cancer drug? [1]

Answer 35

Trastuzumab - rash

Question 36

Describe the effects of HER2 on cardiomyocytes [1]

Answer 36

Normally HER2 inhibits cardiomyocyte apoptosis [1]

Question 37

Describe the cardiotoxic effects of Trastuzamab [2]

Answer 37

Inhibits HER2 cardiomyocyte apoptosis Get a **decline in left ventricular function** AND **congestive heart failure** Need regular cardiac monitoring

Question 38

Explain a draw back of using antibodies as a targeted therapy [1]

Answer 38

Cannot pass the cell membrane and **must be given IV**