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What is SAGE?

Serial analysis of gene expression - counts transcripts and compare gene expression between cell types of tissues 


Outline SAGE

  1. Isolate mRNA and convert to cDNA 
  2. Cut transcript with anchoring enzyme 
  3. Release bp tags using tagging enzyme 
  4. Ligate into plasmids for sequencing
  5. Count tags to estimate relative gene expression 


What is replacing SAGE?

Whole RNA sequencing 


What are the limitations in SAGE?

  • Only transcript levels; not variants 
  • Homologies with other genes
  • May not be in 3' end where SAGE acts


What are three types of diagnostic method?

What are the advantages and disadvangtages of each?

  1. Biopsy- Cheap but can be invasive and may increase risk of metastasis 
  2. Non-invasive imaging, e.g. MRI/CT - Accurate and sensitive, non-invasive but is expensive 
  3. Molecular markers - Sensitive and can be non-invasive but is not available for all cancers


What could biomarkers be used for?

  • Detecting presence of disease
  • Detecting severity of the disease
  • Predict response to treatment 
  • Monitore response to treatment
  • Detect reccurence of disease 


How do traditional cnacer drugs disrupt DNA replication or cell division?

  • Nucleotide analogues
  • Nucleotide synthesis disrupters
  • Topisomerase inhibitors
  • DNA-binding drugs
  • DNA-cross linkers
  • Intercalatin agents
  • Inhibitors of mitosis


How are the traditional cancer drugs seen as selective?

Target according to proliferation rate - which is much higher in cancer cells than in the rest of the body 


What are biologicals?

Treatments which use bodies natural substances to treat cancer. e.g.

  • Hormones and hormone disrupters
  • Receptor blockers
  • Immunostimulators
  • Targeted toxins
  • Gene therapies
  • RNAi


What is immunotherapy?

Boosting the immune response to kill cancer cells


What types of immunotherapy exist?

  • Molecules which are produced as part of immune response made in the lab
  • Vaccinations against cancer cells to train immune system
  • Therapeutic monoclonal antibodies that recognise molecules on the outside of cancer cells 


What is the goal of personalised medicine?

What muts be considered?

Treatment to match each individual patient

  • Is the gene a tumour supressor/tumour promoter 
  • Cell surface or intracellular 
  • Circulating or solid tumour
  • Chemistry of treatment agent
  • Delivery of the treatment?


What is the aim of checkpoint inhibition treatment?

Cancer cells have commonly lost p53 dependent repair and are dependent on DDR. By knockin our DDR in these cells the cancer cells cannot repair damage to DNA and hence traditional treatments, such as chemo, will be very effective on them. Whilst healthy cells will still have p53 repair and hence unaffected


What drugs have been developed for checkpoint inhibition?

  • Chk1 and Chk2 inhibitors 
  • Pi3 Kinase inhibitors 
  • PARP inhibitors 


What drug has been shown to extend life of breast cancer patients?

What does it target?


Internalisation of Her2


What are the two types of lung cancer?

Small cell lung cancer (20%)

Non-small cell lung cancer (80%)


What is commonly overexpressed in NSCLC?



What is oncogene addiction?

Tumour cells that overexpress a pro-survival oncogene become addicted


What percentage of lung cancer patients respond to EGFR inhibitors?



Have mutation in tyrosine kinase domain which causes sensitivity. Other patients have slightly different mutation in same domain which makes them resistant


Why was RNAi seen as having massive promise?

  • Only requires sequence of target to cause destruction 
  • Hence is cheaper and quicker then traditional drug discovery


What are the problems with RNAi?

  • Delivery 
    •  Systemic or topical?
    •  Entry to cell?
    •  Accumulation in organs
  • Stability


Why is DNA replication a good possible target?

The process is dependent on a single set of enzymes rather than the large range of possible ligands and receptors in downstream processes (redundancy)


What is the role of Ciz1?

Links nuclear structures that organise DNA spatially to the enzymes that regulate DNA replication


Why is Ciz1 a good selective target?

Ciz1 has been alternative splices. One of which, in exon 14, is solely seen in cancer cells. This specific sequence can then be targeted by RNAi, however, RNAi is difficult to get into cell in vivo.


How else could Ciz1 be useful in cancer?

As a biomarker 

Antibody for Ciz1 in blood sample - even in stage 1 lung cancer