Growth Factor Receptor Blockade Extra Reading

Question 1

What is the first step in the formation of a metastatic lesion?

Answer 1

Growth of neoplastic cells after the initial transforming event(s) that is first supported with nutrients supplied from the local micro environment.

Question 2

Following growth of neoplastic cells after the initial transforming event(s) that is first supported with nutrients supplied from the local micro environment, what is the next step in formation of a metastatic lesion?

Answer 2

Neovascularisation must occur next for a tumour mass to exceed approximately 2mm^3 in volume; the regulation, synthesis and secretion of tumour angiogenesis factors play a vital role in this process.

Question 3

How does local tumour cell invasion of the surrounding host stroma occurs next via blood and lymphatic vessels and is enhanced by the production of what?

Answer 3

Lytic enzymes such as matrix metalloproteinases (MMPs) and urokinase from either tumour cells or host inflammatory cells.

Question 4

The released tumour cells must arrest in the capillary beds of distant organs by what? (2)

Answer 4

1. Adhering to the exposed subendothelial basement membrane or
2. Adhering to capillary endothelial cells

Question 5

How do Receptor Tyrosine Kinases (RTKs) function?

Answer 5

RTKs bind to specific ligands triggering a conformation change resulting in dimerization of the receptors. Receptor dimerisation brings together the tyrosine kinase catalytic domains (intracellular domains), which phosphorylate each other on tyrosine residues, and activate intracellular signal transduction pathways.

Question 6

Why does activation of phosphatidylinosititide-3-OH kinase by insulin-like growth factor 1 (IGF-1) result in promotion of cell survival?

Answer 6

Pl3’K has a downstream target , the serine-threonine kinase Akt, also known as PKB (protein kinase B), thus promoting cell survival through the activation of anti-apoptotic pathways.

Question 7

The EGFR/ HER is a representative member of which family of receptors?

Answer 7

Tyrosine kinase family receptors.
EGFR was the first receptor described to have tyrosine kinase activity and the first member of the receptor tyrosine kinase family to be sequenced.

Question 8

What is the rationale behind using monoclonal antibody therapy in targeting growth factor receptors?

Answer 8

By selectively targeting the extracellular portion of a receptor, ligand binding and subsequent intracellular signalling can be prevented.

Also, some antibodies subsequently evoke an immune response to the tumour.

Question 9

What is herceptin?

Answer 9

Anti-Her2 receptor monoclonal antibody.

Binding of the Herceptin MAb antibody to the HER-2 receptor results in competitive inhibition of the ligand binding.

Question 10

After activation of the EGFR signalling pathways, ras and raf are activated, how does this result in potentiation of VEGF transcription?

Answer 10

Activation of EGFR signalling, ras and raf —> phosphorylation of c-Fos and c-Jun, leading to increased AP-1 activity –> AP-1 is a transcription factor, which VEGF and IL-8 all share.

Question 11

Newer generation RTK - specific inhibitors compete at what binding site?

Answer 11

The ATP binding site and prevent phosphorylation by blocking the phosphate source, ATP.

Question 12

What are bispecific antibodies?

Answer 12

They are recombinant proteins that contain one bivalent variable region (Fv) arm targeting an epitope on the surface of a tumour cell and another targeting an immune effector cells, such as a T lymphocyte.
BsAb recruit immune effector cells to the tumour target and generate an increased host-tumour interaction, leading to tumour-cell death.

Question 13

What is Catumaxomab/Removab? (4)

Answer 13

1. Trifunctional antibody.
2. Binds both CD3 on Tc cells and EpCAM on adenocarcinomas.
3. Fc region additionally binds to a cell that expresses Fc receptors: macrophages, NK cell etc. Can trigger immune responses.
4. Treats malignant ascites by binding to CD3, EpCAM and immune cells.

Question 14

What are the advantages of using Bispecific antibodites such as Catumaxomab in cancer immunotherapy?

Answer 14

Ordinary monoclonal antibodies do not activate T-lymphocytes because the Fab regions are already used for binding to the tumour cells.

Bispecific antibodies also have a higher cytotoxic potential and bind to antigens which are expressed relatively weekly.

Question 15

What does Catumaxomab/Removab treat?

Answer 15

1. Trifunctional antibody.
2. Binds both CD3 on Tc cells and EpCAM on adenocarcinomas.
3. Fc region additionally binds to a cell that expresses Fc receptors: macrophages, NK cell etc. Can trigger immune responses.
4. Treats malignant ascites by binding to CD3, EpCAM and immune cells.

Question 16

What is a single-chain antibody?

Answer 16

Recombinant protein composed only of Ig heavy and light-chain variable regions linked by a short, flexible polypeptide.

Rapid tumour penetration owing to their small size.

Unlike whole antibodies, they do not show complement system triggered cytotoxicity as they lack an Fc region.

As they can easily penetrate cells, they can be used to target the active sites of enzymes - which whole mAB cannot.

Question 17

How can single chain antibodies be utilised in photothermal therapy to treat HER2 positive breast cancer?

Answer 17

Nanobodies/SC antibodies which can bind to HER2, are coupled to branched gold nanoparticles that absorb light energy and create heat in order to kill cancer cells.

Question 18

How can dominant-negative mutant receptors be used in cancer treatment?

Answer 18

1. Structurally defective receptors can suppress the action of wild-type receptors.
2. Kinase-negative mutant EGFR is internalised following ligand binding but then recycled to membrane surface.
3. Wild-type receptors, which have the ability to activate the specific signalling cascades the ligand signals for, were degraded following internalisation.