9: Biological basis of cancer therapy

Question 1

Explain the main chemotherapeutic and targeted approaches to treating cancer
Explain why many cancer treatments cause side effects and recall approaches to minimise this
Explain the rationale for developing new targets and new drugs in cancer therapy

Answer 1

?

Question 2

Main types of systemic therapy of cancer?

Answer 2

CYTOTOXIC chemotherapy

Targeted therapies

Question 3

Explain cytotoxic chemotherapy, give examples

Answer 3

Cytotoxics select rapidly dividing cells by targeting their DNA (e.g. alkylating agents, anti-metabolites)
Works systemically
Non-selective - affects ALL rapidly dividing cells in body hence side effects

Question 4

Admin of cytotoxic chemo?

Answer 4

IV or mouth
Neoadjuvant = pre op
Adjuvant = post op
Monotherapy or combination

Question 5

What are alkylating agents? Give examples

Answer 5

Add alkyl groups to guanine residues in DNA
Cross-links DNA, prevents it from uncoiling at replication
Triggers apoptosis

e.g. Chlorambucil, temozolomide

Question 6

What are pseudo-alkylating agents? Give examples

Answer 6

Adds PLATINUM to guanine residues
Same mechanism as alkylating
e.g. Cisplatin, carboplatin

Question 7

Side effects of alkylating agents?

Answer 7

Hair loss (not carboplatin)
Nausea, vomiting, diarrhoea
Immunosuppression
Nephro/neurotoxicity

Question 8

How does cisplatin work?

Answer 8

Enters cell via copper channels
Hydrolysis in low Cl- intracelullar environment
Binds to guanine, forms inter/intra-strand cross-links in DNA
p53 triggers apoptosis

Question 9

What are anti-metabolites? Give examples

Answer 9

Purine/pyrimidine/folate antagonists
Blocks DNA replication and transcription
Double-strand breaks and apoptosis

e.g. Gemcitabine (pyrimidine), 6-mercaptopurine (purine)

Question 10

How does gemcitabine work?

Answer 10

Enters cell and is dephosphorylated to form the pyrimidine antagonist which goes into the nucleus and inhibits DNA replication

Also gets DEAMINATED to become TOXIC

Both lead to apoptosis

Used in pancreatic cancer

Question 11

Side effects of anti-metabolites?

Answer 11

Hair loss (alopecia)
Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
Nausea, vomiting, diarrhoea
Palmar-plantar erythrodysesthesia (PPE)
Fatigue

Question 12

What are anthracyclines?

Answer 12

Intercalates (inserts between) nucleotides in DNA/RNA strand - inhibits transcription/translation
Also blocks DNA repair
Generates oxygen free radicals which damage DNA/cell membrane

e.g. Doxorubicin, epirubicin

Question 13

Side effects of anthracyclines?

Answer 13

Cardiac toxicity (arrhythmias, HF)
Alopecia
Neutropenia
Nausea, vomiting, fatigue
Red urine (doxorubicin)

Question 14

What are vinca alkaloids and taxanes?

Answer 14

Microtubule targeting drugs

Vinca alkaloids: inhibit ASSEMBLY of mitotic microtubules
Taxanes: inhibit DISASSEMBLY

Causes mitotic arrest

Question 15

Side effects of microtubule targeting drugs

Answer 15

Nerve damage (neuropathy)
Alopecia
Nausea, vomiting
Bone marrow suppression
Arthralgia, allergy

Question 16

Topoisomerase inhibitors

Answer 16

Topoisomerases: required to prevent torsional strain in DNA during replication/transcription
Induce temporary single/double-strand breaks in DNA
Protect the free ends of DNA from aberrant recombination

Anthracyclines have anti-topoisomerase effects
Specific topoisomerase inhibitors: Topotecan, etoposide
cause PERMANENT DNA breaks

Question 17

Side effects of topoisomerase inhibitors?

Answer 17

Acute cholinergic type syndrome (sweating, abdominal cramps etc.) so give with atropine
Alopecia, nausea, vomiting, fatigue, bone marrow suppression

Question 18

How can growth factor receptor pathways cause cancer?

Answer 18

Over-expression of Her2 (25% of breast cancer) and EGFR (overexpressed in breast and colorectal)

Increased activation of kinase cascade -> cell proliferation

Question 19

Over-expression of which ligand can cause cancer?

Answer 19

VEGF (prostate, kidney, breast)

Increased activation of kinase cascade -> cell proliferation

Question 20

Constitutive (Ligand-independent) activation of which receptor causes cancer?

Answer 20

EGFR (epidermal GF receptors) -> Lung cancer

FGFR (fibroblast) -> Head/neck cancers, myeloma

Question 21

Mechanisms of monoclonal antibody therapy?

Answer 21

Neutralises ligand
Prevents receptor dimerisation (tyrosine kinase)
Causes internalisation of receptor

Question 22

Examples of monoclonal antibodies in cancer?

Answer 22

Avastin (Bevacizumab) - Neutralises VEGF (improves survival in colorectal)

Cetuximab - binds to EGFR

Question 23

What are small-molecule inhibitors?

Answer 23

Bind to kinase domain (intracellular) of tyrosine kinase receptor
Blocks downstream signalling

Can also act on intracellular kinases, affecting cell signalling pathways

Question 24

What is Glivec?

Answer 24

Small molecule inhibitor

Targets ATP-binding region in kinase domain

Question 25

Why is targeted therapy better than cytotoxic?

Answer 25

Block cancer HALLMARKS (e.g. blow flow to tumour, apoptosis resistance) WITHOUT TOXICITY observed with cytotoxics

Question 26

Monoclonal antibodies vs small molecules?

Answer 26

Monoclonal: Highly specific, long half-life (less frequent admin), good for haematological malignancy

Small molecules: Multiple targets (useful for heterogenic tumours), cheaper, oral admin, can target TKs even without extracellular domains or are constitutively activated

Question 27

What is the mechanism of resistance in targeted therapies?

Answer 27

Mutations
Upregulation of parallel pathways
Intrinsic resistance

Question 28

Mechanism of immunotherapy in cancer?

Answer 28

PD-1 expressed on surface of cancer cells
Binding of ligand means cancer cell no longer recognised as foreign

Inhibition of PD receptor/ligand will stimulate immune system

Nivolumab = Anti-PD1 antibody

Question 29

New therapies and why are they better?

Answer 29

Nanotherapies - more effective delivery
Virtual screening - to identify undruggable targets
Immunotherapies
Targeting cancer metabolism