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Y2 Cancer > Biological Basis of Cancer Therapy > Flashcards

Biological Basis of Cancer Therapy Flashcards

1
Q

What are the 5 most common cancers worldwide

A 
Lung
Breast
Bowel
Prostate 
Stomach
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2
Q

What are the main anti-cancer treatment modalities

A

Surgery
Radiotherapy
Chemotherapy
Immunotherapy

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3
Q

What are the types of genetic mutations causing cancer

A

Chromosome translocation
Gene amplification
Point mutations within promoter/enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression - Inheritance

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4
Q

What cytotoxic can be used in cytotoxic chemotherapy

A 
Alkylating agents
Antimetabolites
Anthracyclines
Vinca alkaloids and taxanes
Topoisomerase inhibitors
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5
Q

What can be used in targeted therapies for cancer

A

Small molecule inhibitors

Monoclonal antibodies

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6
Q

How does cytotoxic chemotherapy work

A

Cytotoxics select rapidly dividing cells by targeting their structures (mostly of DNA)
Work systemically
Non-targeted (all rapidly dividing cells)

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7
Q

What are the uses of cytotoxic chemotherapy

A

Given post-operatively: adjuvant
Pre-operatively: neoadjuvant
As monotherapy or in combination
with curative or palliative intent

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8
Q

Describe alkylating agents

A 
Add alkyl (CNH2N+1) groups to guanine in DNA
Cross-link DNA strands and prevents DNA from uncoiling at replication, triggering apoptosis (via checkpoint pathway)
BUT encourages miss-pairing - oncogenic
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9
Q

Describe pseudo-alkylating agents and give examples

A

Add platinum to guanine residues in DNA
Same mechanism of cell death as akylating agents

Examples: carboplatin, cisplatin, oxaliplatin

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10
Q

Give examples of alkylating agents

A

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide

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11
Q

What are the side effects of pseudo-alkylating

A 
Cause hair loss (not carboplatin)
Nephrotoxicity
Neurotoxicity
Ototoxicity (platinums)
Nausea
Vomiting
Diarrhoea
Immunosuppression
Tiredness
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12
Q

Describe anti-metabolites

A

Purine or pyrimidine analogues leading to inhibition of DNA synthesis
DNA double strand breaks and apoptosis
Blocks DNA replication and transcription

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13
Q

Give examples of anti-metabolites

A

methotrexate (folate)
6-mercaptopurine
Decarbazine and fludarabine (purine)
5-fluorouracil, capecitabine, gemcitabine (pyrimidine)

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14
Q

What do folate antagonists do in cancer therapy

A

Inhibits dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids – especially thymine

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15
Q

What are the side effects

A

Hair loss (alopecia) – not 5FU or capecitabine
Bone marrow suppression
Increased risk of neutropenic sepsis or bleeding
Nausea and vomiting
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia (PPE)
Fatigue

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16
Q

What do anthracyclines do

A

Inserts between nucleotides within the DNA/RNA strand
Blocks DNA repair - mutagenic
Creates free oxygen radicals which can damage DNA and the cell membrane

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17
Q

Give examples of anthracyclines

A

Doxorubicin, epirubicin

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18
Q

What do vinca alkaloids and taxanes do

A

Inhibits assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest

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19
Q

What are the side effects of vinca alkaloids and taxanes

A 
Peripheral or autonomic neuropathy
Hair loss
Nausea
Vomiting
Bone marrow suppression
Arthralgia
Allergy
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20
Q

What does bone marrow suppression cause

A

Anaemia
Neutropenia
Thrombocytopenia

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21
Q

What are topoisomerases required for

A

Prevents DNA torsional strain during replication and transcription
Induces temporary single (TOPO1) or double strand (TOPO2) breaks in the phosphodiester backbone of DNA
They protect the free ends of DNA from aberrant recombination events

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22
Q

Give examples of topoisomerase inhibitors

A

TOPO1 - Topotecan, Irinotecan

TOPO2 - Etoposide

23
Q

What are the side effects of topoisomerase inhibitors

A

Hair loss
Nausea, vomiting
Fatigue
Bone marrow suppression

24
Q

What are the side effects of irinotecan and what can be given to alleviate these

A

Acute cholinergic type syndrome: diarrhoea, abdominal cramps and diaphoresis (sweating)

Therefore given with atropine

25
Q

State the mechanisms of resistance to cytotoxic drugs, and give an example for each

A

DNA repair mechanism upregulated so DNA damage repaired – no double strand breaks

DNA adducts replaced via base-excision repair (using PARP)

Drug effluxed from cell by ATP-binding cassette (ABC transporters)

26
Q

Give an example of cytotoxic drugs that may cause resistance due to DNA repair up regulation

A

e.g. 6-mercaptopurine and irinotecan

27
Q

Give an example of cytotoxic drugs that may cause resistance due to DNA adducts replacement

A

e.g. cylophasphamide and veliparib

28
Q

Give an example of cytotoxic drugs that may cause resistance due to drug efflux

A

e.g. Cisplatin or oxaliplatin (MRP1 gene)

29
Q

What is the advantage of dual-kinase inhibitors

A

Most cancers don’t have one specific target – multiple abnormalities
Can stop one pathway in monogenic cancers but other cancers will just use a parallel pathway/feedback cascades to activate
Dual-kinase inhibitors prevent feedback loops (but high toxicity)

30
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
31
Q

How are receptor tyrosine kinases associated with malignancy

A

> 50% associated with human malignancies

Over-expression of receptors (HER2, EGFR)

32
Q

Which cancers are associated with over-expression of HER2, EGFR and PDGFR

A

HER2 – amplified and over-expressed in 25% breast cancer
EGFR – over-expressed in breast and colorectal cancer
PDGFR- glioma (brain cancer)

33
Q

Which cancers are associated with over-expression of ligands

A

VEGF – prostate cancer, kidney cancer, breast cancer

34
Q

Which cancers are associated with constitutive (ligand independent) receptor activation

A

EGFR - lung cancer

FGFR - head and neck cancers, myeloma

35
Q

What are the different types of monoclonal antibodies used in cancer therapy (base on suffix)

A
  • momab (derived from mouse antibodies)
  • ximab (chimeric) e.g cetuximab
  • zumab (humanised) e.g. bevacizumab trastuzumab
  • mumab (fully human) e.g. panitumumab
36
Q

How do monoclonal antibodies work as cancer therapy

A

Target extracellular component of receptor

  • Neutralise ligand
  • Prevent dimerization
  • Cause internalisation of receptor
  • Activating complement-dependent and antibody-dependent cytotoxicity
37
Q

What do small molecule inhibitors do

A

Bind to the kinase domain of the tyrosine kinase within the cytoplasm
Blocks autophosphorylation and downstream signalling

38
Q

What are the advantages of monoclonal antibodies use for cancer therapy

A

Very specific and can be modified to add radiolabels
Metastatic tumours well targeted
Longer half-life

39
Q

What are the disadvantages of monoclonal antibodies use for cancer therapy

A

Risk of immunogenicity and allergy due to use of chimeric forms
IV admin (degrades orally)
Expensive to manufacture
Only useful against external targets
Not useful for constitutively activated targets

40
Q

What are small molecule inhibitors and give an example

A

ATP-mimetics
Glivec/Imantinib – first ”targeted therapy” which targets Bcr-abl – a fusion protein encoded by the Philadelphia chromosome drives overproduction of WBC in chronic myeloid leukaemia

41
Q

What are the advantages of small molecule inhibitors

A

Cheap
Oral administration
Good tissue penetration

42
Q

What are disadvantages of small molecule inhibitors

A

Shorter t1/2 so have to be more frequently administered

↑toxicity which are unexpected

43
Q

Give examples of small molecule inhibitors that inhibit receptors

A

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

44
Q

Give examples of small molecule inhibitors that inhibit intracellular kinases

A

Sorafinib (Raf kinase)

Dasatimib (Src kinase)

45
Q

What are the advantages of targeted therapies

A

Block hallmarks of cancer WITHOUT cytotoxic effects
Targets structures not pathway
E.g. VEGF inhibitors alter blood flow to tumour
AKT inhibitors block apoptosis resistance mechanisms

46
Q

What are the resistance mechanisms to targeted therapy

A

Mutations in ATP-binding domain
Intrinsic resistance
Intragenic mutations
Upregulation of downstream or parallel pathways

47
Q

Describe anti-sense oligonucleotides

A

Single stranded, chemically modified DNA- like molecules
Complementary nucleic acid hybridisation to target gene
Hinders translation of specific mRNA
Recruits Ribonuclease H to cleave mRNA
Good for “undruggable” targets

48
Q

Describe RNA interference

A

Single stranded complementary RNA
Compounds must be packaged to prevent degradation  Nanotherapies
BUT Tumour heterogeneity means different areas may have different molecular profiles

49
Q

Describe b-RAF and its side effects

A

Mutation identified in 60% of melanomas – 500x increase in b-RAF pathway
Vemurafenib – b-RAF inhibitor (SMI)
Side effects: arthralgia, skin rash ,photosensitivity

50
Q

Give examples of new therapies

A

Nanotherapies – deliver cytotoxics more effectively
Virtual screening – to identify “undruggable” targets
Immunotherapies – use antigen presenting cells to present “artificial antigen”
Target cancer metabolism

51
Q

What is the advantage of sequencing tumours before therapy

A

Used to provide treatment as well as prognostic information
Concentrate on particular pathways for certain cancers
Identification of circulating biomarkers, tumour cells or DNA

52
Q

What is the most common toxicity with chemotherapy

A

Bone marrow suppression which leads to neutropenic sepsis

53
Q

How does radiotherapy kill cancer cells and how is it given?

A

High doses of radiation disrupts DNA sequencing by causing double strand and single strand breaks via photons and free radicals.
Given in short, intense doses to minimise radiation to other parts of the body, as well as giving most to the target area

54
Q

Give an example of an immediate, delayed, late and psychological side effect of chemotherapy

A

Immediate - nausea and vomiting,
Delayed – alopecia, lethargy (due to reduced RBC)
Late – Infertility, immunosuppression
Psychological – loss of hair can be difficult to cope with, anticipatory nausea and vomiting due to conditioning, Concerns about effect on friends and family/depression

Y2 Cancer (16 decks)

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