Biological Basis of Cancer Therapy

Question 1

What are the five most common cancers worldwide?

Answer 1

1st- Lung (in men)
1st - Breast  (in women)
western: 
Bowel 
Prostate  
Stomach

Question 2

What are the four main anti-cancer modalities?

Answer 2

Radiotherapy

Chemotherapy

Surgery

Immunotherapy

Question 3

List the different types of cytotoxic chemotherapy.

Answer 3

Alkylating agents

Pseudoalkylating agents

Antimetabolites

Anthracyclines

Vinca alkaloids and taxanes

Topoisomerase inhibitors

Question 4

What are the main types of targeted therapy for cancer?

Answer 4

Monoclonal antibodies

Small molecule inhibitors

Question 5

hat is the term used to describe chemotherapy that is given:

a. Following surgery
b. Before surgery

Answer 5

a. Adjuvant

b. Neoadjuvant

Question 6

How do alkylating agents work?

Answer 6

They add an alkyl group to the guanine residues in DNA

This causes cross-linking of the DNA strands and prevents DNA from uncoiling at replication

This then triggers apoptosis (via a DNA checkpoint pathway)

It encourages mis-pairing

Question 7

Name 3 alkylating agents.

Answer 7

Chlorambucil

Cyclophosphamide

Dacarbazine

Question 8

How do pseudoalkylating agents work?

Answer 8

They have the same mechanism as alkylating agents but use platinum instead of alkyl groups

Question 9

Name three pseudoalkylating agents.

Answer 9

Carboplatin
Cisplatin
Oxaliplatin

Question 10

What are some side effects of alkylating and pseudoalkylating agents?

Answer 10

Alopecia (except carboplatin), 
  Nephrotoxicity, 
Neurotoxicity,  
Ototoxicity (platins), 
Nausea, Vomiting, Diarrhoea, Immunosuppression,  Tiredness

Question 11

How do anti-metabolites work?

Answer 11

They masquerade as purine or pyrimidines leading to inhibition of DNA replication and transcription

They can also be purine/pyrimidine or folate antagonists (dihydrofolate reductase inhibitors-prevents nucleic acid formation)
This blocks DNA replication and transcription

Question 12

Give six examples of anti-metabolites.

Answer 12

Methotrexate- Folate
5-fluorouracil- Pyrimidine
6-mercaptopurine- Purine

Question 13

State some side effects of anti-metabolites.

Answer 13

• Alopecia (not 5-fluorouracil),
• Bone marrow suppression (–> anaemia, neutro/thrombocytopenia)
• Increased risk of neutropenic sepsis,
• Nausea/Vomiting, Mucositis/Diarrhoea, Fatigue,
• Palmar-plantar erythrodysesthesia (PPE)

Question 14

How do anthracyclines work?

Answer 14

They intercalate into DNA or RNA sequences and inhibit transcription and replication

It also blocks DNA repair

They create DNA damaging and cell membrane damaging oxygen free radicals

Question 15

Give two examples of anthracyclines.

Answer 15

Doxorubicin

Epirubicin

Question 16

State some side effects of anthracyclines.

Answer 16

Cardiac toxicity (probably due to the free radicals),  
Alopecia, 
Neutropenia, 
Nausea, Vomiting, Fatigue,  
Red urine (doxorubicin –‘the red devil’)

Question 17

How do vinca alkaloids and taxanes work?

Answer 17

Vinca alkaloids inhibit assembly of microtubules
Taxanes inhibit disassembly of microtubules
This forces the cells into mitotic arrest

Question 18

State some side effects of these drugs.

Answer 18

Nerve damage (peripheral neuropathy and autonomic neuropathy)
Hair loss
Nausea, Vomiting
Bone marrow suppression
Arthralgia (severe joint pain without swelling or signs of arthritis)
Allergy

Question 19

How do topoisomerase inhibitors work?

Answer 19

Topoisomerase is responsible for the unwinding of DNA and they induce temporary single and double strand breaks in the phosphodiester backbone

Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA

Question 20

Give three examples of topoisomerase inhibitors.

Answer 20

Topotecan (topo 1)
Irinotecan (topo 1)
Etoposide (topo 2)

Question 21

State some side effects of topoisomerase inhibitors.

Answer 21

Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis – so they are given with atropine)
Hair loss
Nausea, Vomiting, Fatigue
Bone marrow suppression

Question 22

What are the six hallmarks of cancer?

Answer 22

SPINAP 
Self-sufficient  
Pro-invasive and metastatic  
Insensitive to anti-growth signals  
Non-senescent
Anti-apoptotic  
Pro-angiogenic

Question 23

What are the four hallmarks of cancer that have recently been added?

Answer 23

DIE U 
Dysregulated metabolism 
Inflammation 
Evades the immune system  
Unstable DNA

Question 24

Give three examples of receptors that are over-expressed in cancer.

Answer 24

EGFR – over-expressed in many breast and colorectal cancers

HER2 – breast

PDGFR – glioma (brain)

Question 25

Give an example of a ligand that is over-expressed in some cancers.

Answer 25

VEGF – prostate, kidney and breast cancer

Question 26

Give two examples of constitutive (ligand independent) receptor activation in cancer.

Answer 26

EGFR – lung cancer FGFR – head and neck cancers, myeloma

Question 27

What do each of the following suffixes mean in relation to monoclonal antibodies: a. -momab b. -ximab c. -zumab d. -mumab

Answer 27

a.–momab Derived from mouse antibodies b.–ximab Chimeric antibody c.–zumab Humanised antibody d.–mumab Fully human antibody

Question 28

Describe the structure of humanised monoclonal antibodies.

Answer 28

Murine (mouse) regions are interspersed within the with the light and heavy chains of the Fab portion

Question 29

Describe the structure of chimeric monoclonal antibodies.

Answer 29

The murine component of the variable region of the Fab section is maintained integrally

Question 30

What effect can monoclonal antibodies have on receptors and their activation?

Answer 30

They target the extracellular component of receptors and can prevent receptor dimerization, neutralise the ligand and cause internalisation of the receptor NOTE: they also activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)

Question 31

Give two examples of monoclonal antibodies used in oncology.

Answer 31

Bevacizumab (avastin) – binds and neutralises VEGF Cetuximab – targets EGFR

Question 32

How do small molecule inhibitors work?

Answer 32

They bind to the kinase domain of tyrosine kinase receptors within the cytoplasm and block autophosphorylation and downstream signalling

Question 33

What was the first targeted treatment for cancer and how did it work?

Answer 33

Glivec (imatinib) – it is a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1 This inhibits the kinase activity of ABL1

Question 34

Give four examples of small molecule inhibitors that inhibit receptors.

Answer 34

Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2) Sorafenib (VEGFR)

Question 35

Give three examples of small molecule inhibitors that inhibit intracellular kinases.

Answer 35

Sorafenib (Raf kinase) – this is in addition to its anti-VEGFR effects Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)

Question 36

State some advantages and disadvantages of monoclonal antibodies.

Answer 36

``` Advantages:  High target specificity  Cause ADCC, complement-mediated cytotoxicity and apoptosis induction  Can be radiolabelled  Long half-life  Good for haematological malignancies Disadvantages:  Large and complex structure  Less useful against bulky tumours  Only useful against targets with extracellular domains  Not useful for constitutively activated tumours  Cause immunogenicity and allergy  IV administration  Expensive ```

Question 37

State some advantages and disadvantages of small molecule inhibitors.

Answer 37

Advantages:  Can target tyrosine kinases without an extracellular domain or which are constitutively activated  Pleiotropic targets (useful in heterogenic tumours/cross-talk)  Oral administration  Good tissue penetration  Cheap Disadvantages:  Shorter half-life, more frequent administration  Pleiotropic targets (more unexpected toxicity)

Question 38

State some resistance mechanisms to targeted therapies.

Answer 38

Mutations in ATP binding domain Intrinsic resistance Intragenic mutations Upregulation of downstream signalling pathways

Question 39

Explain how anti-sense oligonucleotides work.

Answer 39

These are short single-stranded DNA-like molecules They bind to the complementary sequence on mRNA and hinder its translation It then recruits RNase H to cleave the target mRNA Mechanism: anti-sense oligonucleotides

Question 40

Name a successful B-Raf inhibitor.

Answer 40

Vemurafenib | NOTE: side effects include arthralgia, skin rash and photosensitivity

Question 41

Explain how the PD-1 receptor-PDL1 ligand system works.

Answer 41

PD-1 receptor is on the cell membrane When the ligand (PDL-1) binds to the PD-1 receptor, the body’s T cells can no longer recognise tumours as foreign So blocking the PD-1 receptor will stimulate the immune system

Question 42

Name a drug that inhibiting PD-1.

Answer 42

Nivolumab (anti-PD1 antibody)

Question 43

what are the resistance mechanisms to cytotoxic chemo drugs

Answer 43

-DNA repair mechanism upregulated so DNA damage repaired – no double strand breaks E.g. 6-mercaptopurine and irinotecan (topo 2) -DNA adducts replaced via base-excision repair (using PARP) E.g. Cyclophasphamide and Veliparib (BRCA) -Drug effluxed from cell by ATP-binding cassette (ABC transporters) E.g. Cisplatin or oxaliplatin (MRP1 gene)