Molecular Targeted Therapy

Question 1

What is the aim of targeted therapy?

Answer 1

To be more precise, targeting specific oncogenic drivers.
These therapies block the growth/spread of cancer by interfering with specific molecules involved in tumour growth and progression. Many are oral therapies often used in combination with surgery/conventional
chemotherapy/radiation.
It is used increasingly at earlier stages. It can be used in an adjuvant setting or a palliative setting.

Question 2

Give some examples of cancer targets. (5)

Answer 2

Tyrosine kinase (intracellular)
Growth factor receptors (extracellular)
Epigenetic modifications
Angiogenesis
Hormone (receptor) (oestrogen/progesterone/androgens)

Question 3

How do monoclonal antibodies work (using named examples)?

Answer 3

Monoclonal antibodies inhibit signalling by binding to the extracellular domain to inhibit growth-factor signalling mediated by the receptor tyrosine kinase is, resulting in arrest in tumour growth.
An example is trastuzumab. It works by preventing cleavage to prevent unregulated signalling pathways being activated, inhibiting dimerization to inactive signalling pathways, antibody-dependent cell mediated cytotoxicity to destroy the tumour cell, and by endocytosis to degrade HER2.

Question 4

What are the differences between naked therapeutic antibodies and antibody drug conjugates?

Answer 4

Naked antibodies work by activating the immune system, targeting immune system checkpoints, and inhibiting the activity of the antigen and preventing growth.
Antibody drug conjugates are efficient carriers for delivery of anti-tumour agents. They are either radiolabelled or chemolabelled.

Question 5

How do tyrosine kinase inhibitors work?

Answer 5

Bind to growth factor receptor and prevent growth signal

Question 6

What are taxanes and vinca alkaloids?

Answer 6

Plant alkaloids

Question 7

What two treatments make up targeted therapy?

Answer 7

Monoclonal antibodies

Small tyrosine kinase inhibitors

Question 8

Best targets are…?
Next best targets…?
What is also possible in terms of targets?

Answer 8

Found in cancer cells but not in normal cells
More targets in cancer cells than normal cells (e.g. gene amplification – overexpression of HER2 or EGFR)
Targets in both cancer and normal cells, but the normal cell regenerates.

Question 9

Which cancers can be targeted? (4)

Answer 9

Breast
Colorectal
Lung
Melanoma

Question 10

How is breast cancer targeted?

Answer 10

13-20% of breast cancers overexpress HER2 due to HER2 gene amplification, so all primary, recurrent and metastatic breast cancers are tested for HER2
Treated with trastuzumab

Question 11

How is colorectal cancer targeted?

Answer 11

35-50% overexpress EGFR

Treated with cetuximab with oxaliplatin-containing chemotherapy

Question 12

How is lung cancer targeted?

Answer 12

15% EGFR positive

Treated with afatinib, erlotinib, gefitinib, bevacizumab

Question 13

How is melanoma targeted?

Answer 13

50% with metastatic melanoma have a BRAF mutation and 20% have intrinsic resistance
Treat with vemurafenib, with trametinib

Question 14

How do receptor tyrosine kinases signal?

Answer 14

The growth factor binds to the extracellular domain and leads to growth, cell death, survival, motility intracellularly

Question 15

What biological therapies are there? (3)

Answer 15

Antibody inhibitors of growth receptors bind to growth factor receptor and prevent growth signal
Antibody-drug conjugates - the antibody targets drug to tumour cells
Tyrosine kinase inhibitors

Question 16

How are antibodies modified for cancer treatment? (3)

Answer 16

Stable linker that release the payload only in target cell
Potent cytotoxic payload
Selective monoclonal antibody that preferentially targets tumour specific or tumour associated antigens

Question 17

How do MaBs work? (3)

Answer 17

Killing tumour cell directly – blocking signalling, inducing apoptosis, delivery of toxic payload
Killing tumour cells via an immune-mediated mechanism – phagocytosis, complement dependent cytotoxicity, antibody dependent cell cytotoxicity
Vascular or stromal ablation – delivery of toxic payload, VEGF antagonism (inhibits angiogenesis)

Question 18

What is VEGF? Why is it relevant in cancer?

Answer 18

Required for formation of nascent blood vessels
One of most upregulated antigens in cancer and functions indirectly as survival factor for tumour cells.
If you inhibit VEGF signalling, you inhibit angiogenesis, so inhibit cell growth and metastasis

Question 19

How can antibodies access tumour cells?

Answer 19

Blood vessels are leaky in tumour tissue, so molecules have access to the tissue. Also tumour tissue doesn’t have lymphatic drainage system, so these molecules are retained and acculumate.

Question 20

A ‘mab’ that ends in ‘mab’ - what does this mean?

What about ending in ‘zumab’?

Answer 20

100% human

Humanized (95%)

Question 21

What does a chimeric mab end in?

Answer 21

ximab (65%)

Question 22

o for…?
a for…?
e for…?
i for…?

Answer 22

Mouse
Rat
Hamster
Primate

Question 23

Small molecule tyrosine kinase inhibitors – what do they do?
What is their major benefit?

Answer 23

Target oncogene product by inhibit signalling at key steps

Safer than chemotherapy

Question 24

What mutation is associated with drug resistance?

Answer 24

Mutations in tyrosine kinase domain of EGFR

Question 25

What are the side effects of targeted therapies?

Answer 25

Skin changes (rashes, dry skin, itchy skin, hand foot syndrome, hair, dry or red eyes)
High blood pressure
Slow wound healing and blood clotting
Congestive heart failure

Question 26

What is the main problem with trastuzamab?

Answer 26

Cardiotoxicity