Cancer Bio (Michaelis Lecture 3 - Drug resistance in cancer) Flashcards
What is the most effective anti cancer therapy?
Surgery
- if cancer is detected early enough/localised tumour
What is a good therapeutic approach for preventing metastasis?
Surgery in addition to chemo/radiotherapy
What therapy is used for cancers that have metastasized?
Systemic therapies
- chemotherapy
What % of cancer cures are achieved by which therapy?
- Surgery 49%
- Local radiotherapy 40%
- Systemic therapy 11%
Give an example of a cancer for which systemic therapy is effective?
Testicular cancer
- Virtually non treatable until 1970s
- Current cure rates of about 95% in the UK
- Cisplatin commonly used
What are the 5 main reasons that cancer is so hard to cure with systemic therapy?
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
A study of drug adherence in patients with breast cancer (2013) followed how many people over how many years taking what drug?
1200 breast cancer patients
Taking tamoxifen for 5 years
What percentage of patients showed low adherence?
38%
Low adherence reduced time to recurrence by what %?
52%
Low adherence was associated with a loss of how many years of life?
1.43 years
Why is the therapeutic window so small for systemic cancer therapies?
Because cancer cells and normal diploid non-malignant cells are so similar
Normal and cancer cells only differ in what ways?
- Genetic stability
- Gene expression
- Activity/proliferation
How are bacteria targeted by therapy?
- Antibiotics target bacterial metabolism
- Distinct from eukaryotic metabolism
- penicillin inhibits cell wall synthesis
How are bacteria targeted by therapy?
- Antivirals target virus-specific structures
How are tumour cells targeted by therapy? Why does this show that the therapeutic window is small?
- 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
How do alkylating agents act as anti-cancer drugs? Give an example of a drug
- Alkylate guanine of DNA, preventing DNA replication - subsequent apoptosis
- ‘Nitrogen mustards’ e.g HN2 (mustine)
How do platinum drugs act as anti-cancer drugs? Give an example drug
- 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
What are the 2 types of tubulin-binding agents?
1) Vinca alkaloids
2) Taxanes
How do Vinca alkaloids work? Give an example drug
- Bind to tubulin dimers and inhibit microtubule assembly
- Vincristine
How to Taxanes work? Give an example drug
- Stabilise microtubule polymers, prevent microtubule disassembly, block mitosis
- Paclitaxel
If cancer drugs kill normal cells, why are cancer therapies effective in some patients?
Because in most cases cancer cells are more sensitive to cytotoxic insult than normal diploid cells
What is it that mean cancer cells are more likely to be resistant to drugs?
- Heterogeneity
- Cancer cells highly adaptable: Genetically and epigenetically unstable
- Large variation
- More variation increases likelihood of drug resistance
What is the pharmacological factor for drug resistance in cancer?
- Normal therapeutic plasma level of drug cannot be achieved
What are some reasons why sometimes effective drug plasma levels cannot be achieved?
- 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
What is the cellular factor of drug resistance?
Cancer cells do not respond to therapeutic drug concentration
What are the 2 types of cellular drug resistance?
1) Intrinsic resistance (present at diagnosis)
2) Acquired resistance (develops during therapy)
What occurs to the tumour size in intrinsic resistance?
Therapy begins but tumour grows
What cancer types are associated with intrinsic resistance?
Pancreas
Melanoma
What occurs to tumor size in acquired resistance?
1) Therapy begins
2) Tumor will either:
- not grow (stabilise)
- Partial remission
- Complete remission
3) However, tumour then grows
What cancers are associated with acquired resistance?
Breast, ovarian
Name some mechanisms of cancer drug resistance?
- Increased drug efflux
- Decreased drug uptake
- Defects in apoptosis signalling
- Enhanced DNA repair
- Decreased expression/mutations of target molecules
- Increased expression of cytoprotective molecules
What transporters are commonly used in cancer cells to cause drug efflux?
ATP binding cassette (ABC) transporters
What drugs were trialed to prevent cancer cell drug efflux?
ABCB1 inhibitors
Why were generation 1 ABCB1 inhibitors rejected?
High dose needed - associated with toxicity
Why were generation 2 ABCB1 inhibitors rejected?
Unpredictable pharmacological interactions
- Non specific binding
Give some overall reasons why ABCB1 inhibitors failed in clinical trials?
- 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
What main 3 cellular mechanisms are altered in cancer cell drug resistance?
- Cell cycle arrest
- Apoptosis
- DNA repair
What is the most common mutation in all cancer cells? How does this act in favour of cancer development?
- 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
What are some examples of DNA repair mechanisms that may be upregulated in response to cancer drugs?
- Reversion repair
- BER
- NER
- Mismatch repair
- DDB repair by homologous recombination or non-homologous end joining
How does reversion repair repair DNA and what type of drugs does this give resistance against?
- MGMT (enzyme) repairs DNA damage at O6 position of guanine residues
- Major resistance against alkylating agents
How is topoisomerase II regulated in cancer cells and why?
- Decreased expression and increased mutations
- Topoisomerase II involved in isomerisation of tertiary DNA structure (“shaping”)
- Anthrecyclines target topoisomerase II
What cytoprotective drugs are upregulated in cancer cells? What drugs to they give resistance to?
- Intracellular detoxification systems:
> Glutathione
> Metallothionein
Resistant to cisplatin
What are the characteristic responses to targeted cancer therapeutics?
- 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
How does resistance develop to imatinib? (inhibits BCR-ABL fusion protein)
- Imatinib can be a ABC transporter subtrate (Imatinib efflux)
- Mutations in the BCR-ABL kinase domain
What is needed to tackle the complexity of cancer and cure more patients?
1) Therapies that avoid/overcome drug resistance
2) Tools to identify the weakness of every cancer cell to design personalised therapies
Describe a modern technique that can be used to monitor cancer drug resistance
- Liquid biopsies
How are liquid biopsies used to monitor resistance?
- Blood sample taken
- Circulating tumour DNA and circulating tumour cells isolated
- Can monitor clonal evolution by looking at changes in mutations over time
What is the Resistant Cancer Cell Line (RCCL) collection? How is it used to combat drug resistance?
- > 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
