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Cell and molecular extras > Lecture 18 Molecular Biology and Cancer > Flashcards

Lecture 18 Molecular Biology and Cancer Flashcards

1
Q

Cancer is the … common cause of death in the developed world

A

2nd

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2
Q

Most common cancer

A

Lung

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3
Q

Causes of cancer

A

Physical, chemical and biological

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4
Q

Physical carcinogens

A

UV

Ionising radiation

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5
Q

Chemical carcinogens

A

asbestos

tobacco smoke

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6
Q

Biological

A

infections from viruses, bacteria, parasites

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7
Q

What is now believed to be causing cancer again

A

viruses 10%

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8
Q

HER stands for

A

Human Epidermal GF Receptors

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9
Q

HER is what type of receptor

A

• Tyrosine kinase receptors

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10
Q

3 domains of the receptor

A

IC tyrosine kinase domain, EC ligand BD, TMD

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11
Q

Name the 4 HER encoded by the human genome

A

HER1,2,3,4

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12
Q

HER are a family of

A

structurally-related cell surface proteins

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13
Q

HER proteins undergo… upon ligand binding

A

undergo a conformational change upon ligand binding

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14
Q

What is the conformation shape change of HER proteins essential for

A

essential for dimerization and signalling

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15
Q

Type of dimers

A

Once ligand binds, the receptor can either homo (e.g. HER3:HER3) or heterodimerise (HER2:HER3).

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16
Q

Dimerisation activates…

A

(via phosphorylation) the tyrosine kinase domain

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17
Q

Different combinations of receptors stimulate different downstream signalling pathways e.g.

A

differentiation, migration, proliferation and cell survival

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18
Q

Which dimer has strongest mitogenic signal

A

HER2:HER3

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19
Q

How does HER2 cause cancer

A

changing expression level of receptor

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20
Q

Describe conformation of HER2

A

In conformation which promotes dimerisation so always in conformation to promote signalling

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21
Q

HERs can be described as

A

proto-oncogenes

22
Q

How do HERs become oncogenic

A
  • Overexpression
  • Mutation
  • HER2 mutant form in rats (neu) causes cancer
23
Q

Breast cancer samples what occurs to the HER2 gene

A

Frequently amplified so get hundreds of copies of the gene = gene amplification

24
Q

Normal breast cancer cells

A

diploid, 2n, 2 copies of gene shown by 2 bright spots

25
Q

Mutant breast cancer cells

A

Mutant – many bright spots, gene amplification

26
Q

The copy number of a gene can be determined using a technique called

A

Fluorescence in situ hybridisation (FISH)

27
Q

Result of gene amplification of HER2

A

increased levels of the receptor 
elevated signalling 
cancer

28
Q

Number of copies of HEr2 per cell in normal breast tissue and cancerous tissue

A

• Normal breast tissue 20,000 copies of the HER2 per cell

Cancerous tissue 2 million copies per cell

29
Q

HER2 is a … for several cancers

A

negative prognostic marker

30
Q

Over expression of HER2 correlates with

A

poor survival rate

31
Q

Median survival for breast cancer patients without treatment

A

(HER2 positive 3 years)/(HER2 normal 6-7 years).

32
Q

What is there strong evidence of if HER2 is overexpressed

A

Strong evidence overexpression of Her2 promotes overexpression of cancer

33
Q

AB interfere with… and target…

A

Antibody binding can interfere with receptor signalling.

Antibody binding can target cells for destruction by the bodies immune system.

34
Q

What is the first step in making a therapeutic antibody

A

making a monoclonal antibody

35
Q

Monoclonal antibodies recognise

A

a single epitope on an antigen

36
Q

How can vast quantities of AB be made?

A

Through a cell line

37
Q

How would you make an AB?

A

Inject mice with Her2 receptor, take spleen cells and fuse with myeloma cells, makes hybridomas which are immortal.

38
Q

What is the issue with murine AB?

A

Immune reaction - not well tolerated in humans

39
Q

Evidence: Targeting HER2 over expressing cancer cells with 4D5 inhibits their growth

A

1) Treating HER2 over expressing cells with the monoclonal antibody (4D5) which binds the extracellular domain of HER2 inhibits their proliferation.
2) Injecting mice with the anti-HER2 monoclonal (4D5) antibody suppresses tumor growth in mice.
3) Injected radio labeled 4D5 targets HER2 positive breast cancer cells in women.

40
Q

Structure of IgG1

A

2 heavy chains and 2 light chains

41
Q

Hypervariable region of AB

A

Involved in antigen binding i.e. bind to HER2

These regions are also called complementary determining regions (CDRs)

42
Q

Up to…CDRs can be involved in binding an antigen

A

• Up to six CDRs can be involved in binding an antigen

43
Q

Humanised version of 4D5 Herceptin (Trastuzumab) - production

A

1) Clone the murine heavy and light chain cDNA encoding anti-HER2 monoclonal (4D5) antibody
2) Clone the murine CDRs of 4D5 into human IgG1 heavy chain and light chain plasmids.
3) The humanised antibody is then made by transfecting CHO cells with light chain and heavy chain plasmids.

44
Q

Phase II clinical trials of Herceptin showed

A
  • Study shows that - –Herceptin is active on women with HER2 positive breast cancer
    However, it did not show any benefit on women who had normal levels of HER2.
    Genentech and DAKO develop a diagnostic test for determining HER2 expression levels
45
Q

Phase III clinical trials showed

A

Showed women with HER2 positive breast cancer gain extra 5 months disease free survival
However, Herceptin can cause serious complications as needed for normal heart function
Cancer returns in the majority of the women.

46
Q

Why were more clinical trials carried out

A

• To investigate the best way to use Herceptin
- Herceptin is most effective if used in combination with surgery or chemotherapy for 1 year
- 85% cancer free after 5 years vs 66% with just Herceptin
• To determine if Herceptin works on other HER2 positive cancers (indications).
- It can be used in metastatic gastric cancer

47
Q

How does Herceptin work

A

Herceptin binds to the EC domain of the HER2 receptor and:
• Interferes with IC signalling, hence inhibiting proliferation of the receptor
• Targets cells for antibody-dependent cell-mediated cytotoxicity (ADCC) which flags the receptor for destruction
• Inhibits EC domain shedding

48
Q

Cancer returns in …%

A

15-25%

49
Q

Cancer returning is… to Herceptin/chemotherapy

A

resistant

50
Q

Future direction of treatment

A

1) HER2 dimerisation inhibitors (in combination with chemo/Herceptin)
2) Antibody drug conjugates - Trastuzumab emtansine delivers toxic drug to HER2 positive tumors
3) Targeting other HER family members
4) Drug combinations
- Giving Herceptin plus tyrosine kinase inhibitor (Tyverb) got rid of HER2 positive tumors within 11 days

51
Q

HER2 screening is a good example of

A

personalised medicine in action

Cell and molecular extras (16 decks)

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