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3rd Year Biomed > Cancer Bio (Michaelis Lecture 3 - Drug resistance in cancer) > Flashcards

Cancer Bio (Michaelis Lecture 3 - Drug resistance in cancer) Flashcards

1
Q

What is the most effective anti cancer therapy?

A

Surgery

- if cancer is detected early enough/localised tumour

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2
Q

What is a good therapeutic approach for preventing metastasis?

A

Surgery in addition to chemo/radiotherapy

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3
Q

What therapy is used for cancers that have metastasized?

A

Systemic therapies

- chemotherapy

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4
Q

What % of cancer cures are achieved by which therapy?

A
  • Surgery 49%
  • Local radiotherapy 40%
  • Systemic therapy 11%
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5
Q

Give an example of a cancer for which systemic therapy is effective?

A

Testicular cancer

  • Virtually non treatable until 1970s
  • Current cure rates of about 95% in the UK
  • Cisplatin commonly used
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6
Q

What are the 5 main reasons that cancer is so hard to cure with systemic therapy?

A

1) Medication adherence (whether patients take their drugs as prescribed)
2) Small therapeutic window due to similarity to normal cells
3) Lack of understanding of anti-cancer drugs
4) Each cancer disease is a very complex individual disease
5) Drug resistance

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7
Q

A study of drug adherence in patients with breast cancer (2013) followed how many people over how many years taking what drug?

A

1200 breast cancer patients

Taking tamoxifen for 5 years

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8
Q

What percentage of patients showed low adherence?

A

38%

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9
Q

Low adherence reduced time to recurrence by what %?

A

52%

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10
Q

Low adherence was associated with a loss of how many years of life?

A

1.43 years

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11
Q

Why is the therapeutic window so small for systemic cancer therapies?

A

Because cancer cells and normal diploid non-malignant cells are so similar

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12
Q

Normal and cancer cells only differ in what ways?

A
  • Genetic stability
  • Gene expression
  • Activity/proliferation
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13
Q

How are bacteria targeted by therapy?

A
  • Antibiotics target bacterial metabolism
  • Distinct from eukaryotic metabolism
  • penicillin inhibits cell wall synthesis
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14
Q

How are bacteria targeted by therapy?

A
  • Antivirals target virus-specific structures
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15
Q

How are tumour cells targeted by therapy? Why does this show that the therapeutic window is small?

A
  • Tumour cells and normal cells so similar
  • Anti-cancer drugs mostly target both cancer and normal cells
    e. g targetting of DNA integrity or cell division in unspecific manner
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16
Q

How do alkylating agents act as anti-cancer drugs? Give an example of a drug

A
  • Alkylate guanine of DNA, preventing DNA replication - subsequent apoptosis
  • ‘Nitrogen mustards’ e.g HN2 (mustine)
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17
Q

How do platinum drugs act as anti-cancer drugs? Give an example drug

A
  • Pt reacts with DNA bases (preferentially guanine) resulting in intra and inter DNA cross linking
  • Inhibits mitosis
  • Causes apoptosis if DNA cannot be repaired
  • Cisplatin, carboplatin
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18
Q

What are the 2 types of tubulin-binding agents?

A

1) Vinca alkaloids

2) Taxanes

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19
Q

How do Vinca alkaloids work? Give an example drug

A
  • Bind to tubulin dimers and inhibit microtubule assembly

- Vincristine

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20
Q

How to Taxanes work? Give an example drug

A
  • Stabilise microtubule polymers, prevent microtubule disassembly, block mitosis
  • Paclitaxel
21
Q

If cancer drugs kill normal cells, why are cancer therapies effective in some patients?

A

Because in most cases cancer cells are more sensitive to cytotoxic insult than normal diploid cells

22
Q

What is it that mean cancer cells are more likely to be resistant to drugs?

A
  • Heterogeneity
  • Cancer cells highly adaptable: Genetically and epigenetically unstable
  • Large variation
  • More variation increases likelihood of drug resistance
23
Q

What is the pharmacological factor for drug resistance in cancer?

A
  • Normal therapeutic plasma level of drug cannot be achieved
24
Q

What are some reasons why sometimes effective drug plasma levels cannot be achieved?

A
  • Low pro-drug activation in liver
  • High metabolism of drug or high excretion
  • Tumour microenvironment (lack of vascularisation, hypoxia, diffusion)
  • Physiological barriers e.g. blood-brain barrier, intestines
25
Q

What is the cellular factor of drug resistance?

A

Cancer cells do not respond to therapeutic drug concentration

26
Q

What are the 2 types of cellular drug resistance?

A

1) Intrinsic resistance (present at diagnosis)

2) Acquired resistance (develops during therapy)

27
Q

What occurs to the tumour size in intrinsic resistance?

A

Therapy begins but tumour grows

28
Q

What cancer types are associated with intrinsic resistance?

A

Pancreas

Melanoma

29
Q

What occurs to tumor size in acquired resistance?

A

1) Therapy begins
2) Tumor will either:
- not grow (stabilise)
- Partial remission
- Complete remission
3) However, tumour then grows

30
Q

What cancers are associated with acquired resistance?

A

Breast, ovarian

31
Q

Name some mechanisms of cancer drug resistance?

A
  • Increased drug efflux
  • Decreased drug uptake
  • Defects in apoptosis signalling
  • Enhanced DNA repair
  • Decreased expression/mutations of target molecules
  • Increased expression of cytoprotective molecules
32
Q

What transporters are commonly used in cancer cells to cause drug efflux?

A

ATP binding cassette (ABC) transporters

33
Q

What drugs were trialed to prevent cancer cell drug efflux?

A

ABCB1 inhibitors

34
Q

Why were generation 1 ABCB1 inhibitors rejected?

A

High dose needed - associated with toxicity

35
Q

Why were generation 2 ABCB1 inhibitors rejected?

A

Unpredictable pharmacological interactions

- Non specific binding

36
Q

Give some overall reasons why ABCB1 inhibitors failed in clinical trials?

A
  • Unpredictable interactions between inhibitors and anti-cancer drugs
  • Interaction with other ABCB1 expressed at relevent physiological barriers
  • Interactions with numerous other non-cancer related drugs
  • Cancer cells express multiple ABC transporters - limited effectiveness
37
Q

What main 3 cellular mechanisms are altered in cancer cell drug resistance?

A
  • Cell cycle arrest
  • Apoptosis
  • DNA repair
38
Q

What is the most common mutation in all cancer cells? How does this act in favour of cancer development?

A
  • Mutations in p53
  • p53 is a tumour suppressor protein
  • Acts to inhibit DNA repair, cell cycle arrest and apoptosis
  • Mutant p53 inhibits its normal function
39
Q

What are some examples of DNA repair mechanisms that may be upregulated in response to cancer drugs?

A
  • Reversion repair
  • BER
  • NER
  • Mismatch repair
  • DDB repair by homologous recombination or non-homologous end joining
40
Q

How does reversion repair repair DNA and what type of drugs does this give resistance against?

A
  • MGMT (enzyme) repairs DNA damage at O6 position of guanine residues
  • Major resistance against alkylating agents
41
Q

How is topoisomerase II regulated in cancer cells and why?

A
  • Decreased expression and increased mutations
  • Topoisomerase II involved in isomerisation of tertiary DNA structure (“shaping”)
  • Anthrecyclines target topoisomerase II
42
Q

What cytoprotective drugs are upregulated in cancer cells? What drugs to they give resistance to?

A
  • Intracellular detoxification systems:
    > Glutathione
    > Metallothionein

Resistant to cisplatin

43
Q

What are the characteristic responses to targeted cancer therapeutics?

A
  • High response rates
  • Low side effects (relative to systemic therapy)
  • Personal medicine (only used in patients with tumours that have drug target)
  • Rapid resistance development
  • Multiple targeted therapies can be used to combat resistance
44
Q

How does resistance develop to imatinib? (inhibits BCR-ABL fusion protein)

A
  • Imatinib can be a ABC transporter subtrate (Imatinib efflux)
  • Mutations in the BCR-ABL kinase domain
45
Q

What is needed to tackle the complexity of cancer and cure more patients?

A

1) Therapies that avoid/overcome drug resistance

2) Tools to identify the weakness of every cancer cell to design personalised therapies

46
Q

Describe a modern technique that can be used to monitor cancer drug resistance

A
  • Liquid biopsies
47
Q

How are liquid biopsies used to monitor resistance?

A
  • Blood sample taken
  • Circulating tumour DNA and circulating tumour cells isolated
  • Can monitor clonal evolution by looking at changes in mutations over time
48
Q

What is the Resistant Cancer Cell Line (RCCL) collection? How is it used to combat drug resistance?

A
  • > 1000 cancer cell lines for 15 cancer entities
  • Exposure to increasing drug concentrations
  • Readily growing resistance models
  • Uses both cytotoxic and targeted drugs

Aim:
> discovery of markers of drug resitance
> Identification of next-line therapy

3rd Year Biomed (44 decks)

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