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Cancer > 9. Biological basis of cancer therapy > Flashcards

9. Biological basis of cancer therapy Flashcards

1
Q

What is the leading cause of cancer death in the UK?

A

Lung cancer (regardless of sex)

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2
Q

How is the incidence of cancer set to change in the future?

A
  • General increase

* Reduction in infection-based cancer - will increase Western cancer prevalence (breast, colorectal, lung, prostate)

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3
Q

What are the main cancer treatment modalities?

A
  • Surgery
  • Chemotherapy
  • Radiotherapy
  • Immunotherapy
  • Some with endocrine therapy
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4
Q

What are the 2 types of chemotherapy?

A
  • Cytotoxic - kills the cells e.g. alkylating agents, taxanes, topoisomerase inhibitors
  • Targeted therapies e.g. small molecule inhibitors, monoclonal antibodies
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5
Q

What cells do mainly cytotoxics target?

A
  • Rapidly dividing cells by targeting their structure (mostly DNA)
  • e.g. affects the gut mucosa - mucositis
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6
Q

When is cytotoxic therapy administered?

A
  • Curative or palliative intent
  • Single agent (monotherapy)
  • Pre-operatively e.g. to reduce tumour size for ease (neoadjuvant chemotherapy)
  • Post-operatively e.g. to reduce recurrence (adjuvant chemotherapy)
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7
Q

How do alkylating agents work?

A
  • Add alkyl groups to guanine residues in DNA
  • Causes cross-linking of DNA strands
  • Prevents DNA from uncoiling at replication
  • Triggers apoptosis (via checkpoint pathway)
  • e.g. decarbazine
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8
Q

What is the ironic problem with alkylating agents?

A
  • Can lead to secondary cancers (encourage miss-pairing => oncogenic)
  • However, benefits outweigh the risks
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9
Q

How are pseudo-alkylating agents different to alkylating agents?

A
  • Add platinum to guanine residues in DNA, instead of an alkyl group
  • Follow same mechanism of cell death
  • e.g. carboplatin, cisplatin
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10
Q

What are the side effects of (psuedo-)alkylating agents?

A
  • Hair loss (not carboplatin)
  • Nephrotoxicity
  • Neurotoxicity
  • Ototoxicity (ear)
  • Nausea
  • Diarrhoea
  • Immunosuppression
  • Tiredness
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11
Q

How does cisplatin specifically work?

A
  • Enters cell through copper channels
  • Hydrolysis occurs in the low Cl- intracellular environment - loses a Cl
  • Binds to guanine residues and cross-links DNA
  • Nucleotide excision repair occurs
  • Results in unsuccessful cycles of DNA repair and cell undergoes apoptosis
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12
Q

How do anti-metabolites work?

A
  • Pretend to be purine/pyramidine residues
  • Incorporate into DNA => inhibition of DNA replication and transcription
  • Can be folate antagonist - inhibits dihydrofolate reductase required to make folic acid
  • Folic acid is important for nucleic acid formation
  • DNA double strand breaks
  • Error recognised at DNA checkpoint => apoptosis
  • e.g. methotrexate, 6-MP, decarbazine
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13
Q

What are the side effects of anti-metabolites?

A
  • Hair loss (alopecia)
  • Bone marrow suppression causing anaemia etc.
  • Increased risk of neutropenic sepsis or bleeding
  • Nausea and vomiting (dehydration)
  • Mucositis and diarrhoea
  • Palmar-plantar erythrodysesthesia
  • Fatigue
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14
Q

How do anthracyclines work?

A
  • Intercalate nucleotides within the DNA/RNA strand, inhibiting transcription and replication
  • Block DNA repair (mutagenic)
  • Create DNA and cell membrane damaging free oxygen radical
  • e.g. doxorubicin
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15
Q

What are the side effects of anthracyclines?

A
  • Cardiac toxicity (probably due to free radicals)
  • Alopecia
  • Neutropenia
  • Nausea and vomiting
  • Fatigue
  • Skin changes
  • Red urine
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16
Q

How do vinca alkaloids and taxanes work?

A

• Vinca alkaloids inhibit assembly of mitotic microtubules
• Taxanes inhibit depolymerisation of mitotic microtubules
• Causes dividing cells to undergo mitotic arrest
e.g. paclitaxel, vinorelbine

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17
Q

What are the side effects of microtubule-targeting drugs?

A
  • Nerve damage (peripheral and autonomic neuropathy)
  • Hair loss
  • Nausea
  • Vomiting
  • Bone marrow suppression
  • Arthralgia (joint pain)
  • Allergy
18
Q

What do topoisomerases do and how do topoisomerase inhibitors work?

A
  • Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription
  • They induce temporary single strand (topo1) or (topo2) breaks in the phosphodiester backbone
  • They protect the free ends of DNA from aberrant recombination events
  • Topotecan (topo1) and etoposide (topo2) alter the binding of the complex to DNA
  • This allows permanent DNA breaks
  • Causes apoptosis at DNA checkpoints
  • Anthracyclines also have anti-topoisomerase effects
19
Q

What are the side-effects of topoisomerase inhibitors?

A
  • Acute cholinergic type syndrome - irinotecan (diarrhoea, cramps, diaphoreses [sweating]), therefore given with atropine
  • Hair loss
  • Nausea and vomiting
  • Fatigue
  • Bone marrow suppression
20
Q

What can cause resistance to chemotherapy?

A
  • Up-regulation of DNA repair mechanisms
  • DNA adducts may be replaced by base excision repair (using PARP)
  • Drugs may be effluxed by ATP-binding cassette (ABC) transporters
21
Q

What do we do if a patient of chemotherapy has a fever?

A
  • Give antibiotics ASAP

* Risk of neutropenic sepsis

22
Q

What type of inhibitors are being developed to interfere with cancer cell wiring, and what are the problems with these?

A
  • Dual kinase inhibitors
  • Block 2 pathways
  • Prevent feedback loops
  • Problem - increased toxicity
23
Q

What are the 6 hallmarks of the cancer cell?

A
  • Self-sufficient
  • Insensitive to anti-growth signals
  • Anti-apoptotic
  • Pro-invasive and metastatic
  • Pro-angiogenic
  • Non-senescent
24
Q

In which cancers are the following receptors over-expressed:
• HER2
• EGFR
• PDGFR

A
  • HER2 - breast cancer
  • EGFR - breast and colorectal cancer
  • PDGFR - glioma
25
Q

Why does over-expression of receptors lead to cancer (2 basic steps)?

A

• Over-expression
=> increased kinase cascade
=> increased signal amplification

26
Q

Give examples of how the over-expression of ligands can cause cancer?

A

• VEGF - prostate, kidney and breast cancer
=> increased kinase cascade
=> increased signal amplification

27
Q

Where can ligand-independent receptor activation be seen?

A
  • EGFR in lung cancer

* FGFR in head + neck cancers and myeloma

28
Q

What do the following suffixes for monoclonal antibodies mean:

  • momab
  • ximab
  • zumab
  • mumab
A
  • momab = derived from mouse antibodies
  • ximab = chimeric
  • zumab = humanised
  • mumab = fully human
29
Q

What are humanised monoclonal antibodies?

A
  • Antibodies from non-human species - protein sequences modified to increase their similarity to human antibody
  • Murine regions interspersed with light and heavy chains of Fab portion
30
Q

What are chimeric monoclonal antibodies?

A

Made by fusing the antigen binding region (variable domains) from one species (mouse) with the constant domain from another species

31
Q

Which part of the receptor does the monoclonal antibody target and what does this cause?

A
  • Extracellular domain
  • Neutralises the ligand
  • Prevents dimerisation of the receptor
  • Causes the receptor to be internalised into the cell
  • Also activate Fcγ-receptor-dependent phagocytosis
  • Cytolysis induces complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity
32
Q

What does bevacizumab and cetuximab do?

A
  • Bevacizumab - binds and neutralises VEGF (colorectal)

* Cetuximab - targets EGFR (colorectal)

33
Q

How do small molecule inhibitors work?

A
  • Bind to the kinase domain of the tyrosine kinase in the cytoplasm
  • Affect both receptor TKs and intracellular kinases
  • Blocks auto-phosphorylation and downstream signalling
  • e.g. Glivec (imatinib)
34
Q

What does Glivec specifically target?

A
  • Small molecule inhibitor that targets the ATP binding region within the kinase domain
  • Could target BCR-ABL - (9,22) chromosomal translocation in CML, without affecting other proteins
  • Example of oncogene addiction - uniquely hyperactive oncogene/pathway driving a tumour
35
Q

How is the toxicity of VEGF and AKT inhibitors different to general cytotoxics?

A

VEGF alters the blood flow to tumours and AKT inhibitors block apoptosis resistance without toxicity observed with cytotoxics

36
Q

What are the mechanisms of resistance to targeted therapies?

A
  • Mutations in ATP-binding domain
  • Intrinsic resistance
  • Intragenic mutations
  • Up-regulation of downstream or parallel pathways
37
Q

How do anti-sense oligonucleotides work in cancer therapy?

A
  • They are single stranded, chemically modified DNA-like molecules
  • Cause complementary nucleic acid hybridisation to target gene
  • Recruits RNase H to cleave target mRNA
  • This hinders translation of specific mRNA
38
Q

Why do single stranded complementary RNA need to be packaged for anti-sense technology (cancer therapy)?

A

Prevent degradation

39
Q

What mutation do 60% of melanomas have and why is this significant in therapy?

A
  • B-Raf mutation - substitution of glutamic acid for valine

* Therefore B-Raf inhibitors (vemurafenib) have been successful in treatment - life span extended by 7 months

40
Q

What is PD-1 and why is it significant in cancer therapy?

A
  • Ligand that is present on cancer cells
  • If PD-1 binds to PD-1 receptor, T cell can no longer recognise tumour cells as foreign
  • If either are blocked, the immune system will be stimulated
  • Nivolumab is an anti-PD-1 antibody, which can do this
41
Q

How effective is nivolumab?

A
  • Good results in non-small cell lung cancer, melanoma and renal cell carcinoma
  • Median survival of 16 months (very good for phase I trial)
42
Q

What new ideas are there for future cancer therapy?

A
  • Nano-therapy
  • Virtual screening to identify ‘undruggable’ targets
  • Immunotherapies using antigen presenting cells
  • Targeting cancer metabolism
  • Sequencing tumours prior to starting therapy - concentrate on particular pathways

Cancer (15 decks)

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