Unit 7 - Emerging Targets Flashcards
Discuss the principle of photodynamic therapy
Where a photosensitizer is administers to a patients which after a period of time will accumulate at the target tissue. Light of a specific wavelength will then be used to activate the photosensitizer – which will result in excitation and the production of ROS which can cause DNA damage and activate cell death pathways.
Examples – phenothiazinium salts
What are the 4 key characteristics of a photosensitizer?
- Selectively accumulate in tumour cells
- Minimal dark toxicity
- Strong photo-cytotoxicity
- Wavelength activation should be between 600-800nm
What are the advantages of photodynamic therapy?
- Minimally invasive
- Few side effects
- Cosmetically better than surgery/radiotherapy
- Radiosensitizer has short half-life
- Relatively low cost
- Can be used with standard care
- Can be used in the same location several times
Discuss the importance of MMPs in cancer progression
- Promote tumour proliferation through release of growth factors
- Evade apoptosis by proteolytic inactivation of Fas receptors
- Promote angiogenesis
- Promote cell invasion by degradation of ECM and cell-adhesions
Name one of the original MMP inhibitors and describe the reasons these trials failed
- Batimatastat/marimastat
- At the time only 3 MMPs were known
- Lack of MMP subtype specificity
- Faulty design of clinical trials (patients had advanced disease and differences between mouse and human models)
- Dose-limiting toxicity
- Inhibition of anti-targets (MMP9/12/19 prevent angiogenesis)
How can MMPIs become more specific?
- Due to the fact we now know about the various specificity sites – we can make the agents even more specific
- Can add certain groups like phosphonate to go to specific tissues like the bone (binds to calcium)
- Antibodies preventing interactions between MMPs and their ligands
Describe the purpose of MMP activated pro-drugs in cancer treatment and what characteristics must they have?
Molecules can be designed which contain certain molecules in an inactive form – and are activated by a specific protease that is overexpressed by the tumour of interest – specificity of treatment!! This may also be aided by a ligand to bind to a specific receptor – to further increase specificity!!!
- Enzyme must be well characterised and cleavage preference known
- Protease is present and elevated in the tumour microenvironment but low in normal tissue
- It is absent or inactive in circulation
- It shows high affinity and selectivity for the target
What are ADAMs and what role can they play in cancer progression?
A disintegrin and metalloproteinase – multidomain transmembrane proteins that play roles in cell signalling and migration. Has SH2 (p) and SH3 (proline rich) BINDING REGIONS. Can cleave specific ECM targets.
ADAMs play an important role in EGFR activation
GPCRs can activate 2nd messengers and src to activate ADAMs (intracellular p-Tyr) which cleave these membrane bound ligands (HB-EGF) which allows them to activate EGFR ->PI3K and MAPK activation!!
Discuss the advantages and disadvantages of targeting ADAMs
Advantages
- Decreased proliferation due to less activation of EGFR
- Decreased tumour cell migration due to less cleavage of ECM and cell-adhesions and less CD44
- Increase immune surveillance
- Decrease chemokine agonists in inflammation
- Regulated intramembrane proteolysis may lead to proliferative signalling/activity
Disadvantages
- Decrease soluble antagonists – TNFR
- Decreased neuroprotection/regeneration
Discuss the possibility of ADAM15 targeting in cancer treatment
Is overexpressed in many cancers (including breast) which regulates endothelial cell permeability. Interact with collogens, receptors, cadherins as well as Src and Erk!!!
There are 5 splice variants (A-E) with different intracellular domains. ADAM15B is associated with reduced PFS in node-negative patients whilst ADAM15C in node-positive patients is associated with better outcome. B can bind to Src resulting in FGFR2 which is a tumour suppressor in breast cancer!!
But given some are beneficial and some are not – this likely means its not a good target!!!
Discuss the possibility of combination therapy with ADAM related therapy.
High ADAM activity is seen in cells with BRAF/KRAS mutations -leading to MET/Axl cleavage (poor prognosis). Cells treated with MEK inhibitors have reduced shedding of Met and Axl so they could activate Akt/Fos-Jun.
Hence block TIMPs and MAPK inhibition!
Discuss the role of ZIP7 in cancer
Is overexpressed in breast cancer and associated with Ki67 and anti-hormone resistance. Is phosphorylated by CK2 (S275/276) resulting in opening, release into the ER -> mitosis!
Hence Ck2 inhibitors could be useful!
Discuss why ZIP6 might be a good target in cancer?
It is involved in EMT
Is expressed by ER activity and is found on the ER membrane until cleavage -> plasma membrane. The zinc activity inhibits GSK-3β (along with Akt signalling) resulting in it not being able to phosphorylate SNAIL – so it stays in the nucleus and expresses genes associated with EMT (and blocks E-cadherin expression).
It also does this by interacting with ZIP10 and NCAM which can also inhibit GSK-3β – preventing NCAM phosphorylation and reduces interactions with integrins resulting in a loss of cell adhesion
It is involved in driving mitosis
- In interphase ZIP6 and ZIP10 expression is increased due to STAT3 signalling. This receptors sit on the ER with Jarid1B until a signal causes them to be cleaved and translocate to the cell membrane
- The resulting influx of zinc results in the changing of pS705STAT3->pS727STAT3 which binds to this heteromer.
- pS38Stathmin is also bound to this and responsible for microtubule reorganisation
- This results in the displacement of Jarid1B which is able to bind to histone H3 and take part in chromosome condensation
- Once mitosis has started a further cleavage of the ZIP6 N-terminus
- At the end of mitosis, the N-terminus of STAT3 is cleaved, removing the S727 residue so it restores its transcriptional activity in the pS705 form.
What is epigenetics?
Stable, heritable phenotype resulting from changes in chromosome structure rather than alterations in the DNA sequence
What are the potential advantages of targeting epigenetics in cancer treatment?
- There are a considerable number of mutations in epigenetic regulators involved in driving cancers
- Epigenetic modifications are largely reversible
- Mutations in a single epigenetic regulator are prevalent in a broad range of cancers and responsible in regulating many genes
