Biological Basis of Cancer Therapy

Question 1

What are the five most common cancers worldwide?

Answer 1

Lung Breast 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

What 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

How do pseudo-alkylating agents work?

Answer 7

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

Question 8

What are some side effects of alkylating and pseudoalkylating agents?

Answer 8

Alopecia (hair loss) except carboplatin Nephrotoxicity Neurotoxicity Ototoxicity (toxic to ear) - applies to platinums Nausea, Vomiting, Diarrhoea, Immunosuppression, Lethargy

Question 9

How do anti-metabolites work?

Answer 9

They masquerade as purine or pyrimidines leading to inhibition of DNA replication and transcription They can also be folate antagonists (dihydrofolate reductase inhibitors) This blocks DNA replication and transcription, causing double strand breaks and apoptosis

Question 10

State some side effects of anti-metabolites.

Answer 10

Alopecia (hair loss) - not 5-fluorouracil or capecitabine Bone marrow suppression Increased risk of neutropenic sepsis Nausea, Vomiting, Diarrhoea, Fatigue Mucositis (painful inflammation and ulceration of the mucous membranes lining the digestive tract) Palmar-plantar erythrodysesthesia (PPE)

Question 11

How do anthracyclines work?

Answer 11

They intercalating (iinsert between) 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 12

State some side effects of anthracyclines.

Answer 12

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

Question 13

How do vinca alkaloids and taxanes work?

Answer 13

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

Question 14

State some side effects of vinca alkaloids and taxanes

Answer 14

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

Question 15

How do topoisomerase inhibitors work?

Answer 15

Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA They protect the free ends of DNA from aberrant recombination events Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA

Question 16

State some side effects of topoisomerase inhibitors.

Answer 16

irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis) Alopecia (hair loss) Nausea, Vomiting, Fatigue Bone marrow suppression

Question 17

What are the six hallmarks of cancer?

Answer 17

SPINAP

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

Question 18

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

Answer 18

DIE U

• Dysregulated metabolism
• Inflammation
• Evades the immune system
• Unstable DNA

Question 19

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

Answer 19

EGFR – over-expressed in many breast and colorectal cancers HER2 – breast PDGFR – glioma (brain)

Question 20

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

Answer 20

VEGF – prostate, kidney and breast cancer

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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 or antibody-dependent cellular cytotoxicity (ADCC)

Question 23

Give two examples of monoclonal antibodies used in oncology.

Answer 23

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

Question 24

How do small molecule inhibitors work?

Answer 24

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

Note:

These can be kinase receptors such as EGFR or intracellular kinases such as raf

Question 25

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

Answer 25

Glivec (imatinib) – it is a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1 protein translated from the philidelphia chromosome This inhibits the kinase activity of ABL1 Great results for treating chronic myeloid leukaemia

Question 26

State some advantages and disadvantages of monoclonal antibodies.

Answer 26

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 27

State some advantages and disadvantages of small molecule inhibitors.

Answer 27

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 28

State some resistance mechanisms to targeted therapies.

Answer 28

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

Question 29

Explain how anti-sense oligonucleotides work.

Answer 29

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

Question 30

Name a successful B-Raf inhibitor.

Answer 30

Vemurafenib - treatment of melenomas NOTE: side effects include arthralgia, skin rash and photosensitivity

Question 31

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

Answer 31

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 32

Name a drug that inhibiting PD-1.

Answer 32

Nivolumab (anti-PD1 antibody)

Question 33

How are the side effects of irinotecan overcome?

Answer 33

Administer atropine