Therapeutic Targeting CNS Tumours Flashcards
Challenges for the treatment of brain tumours?
- BBB
- Tumour resistance
- Heterogeneity
- Diffusing nature of some tumours
- Invasive of local delivery to the brain
What properties of drugs are needed to cross BBB?
Lipophilic and low molecular weight
Can chemotherapy drugs cross BBB?
Not well at all
Common anti cancer drug?
Temozolomide
Why p-glycoproteins are barrier to chemotherapy?
Act as efflux pumps, pumping anti-cancer drugs out of the tumours
Potential solutions to improve chemotherapeutic drug delivery?
- Intracranial infusion of arabinose/mannitol
- Convection enhanced therapy (CED)
- Polymeric Vesicles
Properties of glioblastoma?
Very invasive and very aggressive (WHO classfied as grade IV glioma)
Tumour cells___: receive nutrients via diffusion
Tumour cells ___: require their own vasculature
Tumour cells <2mm: receive nutrients via diffusion
Tumour cells >2mm: require their own vasculature
Vascular targets in endothelial cells?
VEGF and VEGFR receptors, αvβ3 and αvβ5 integrins, MMP-2, MMP-9, EGFR
Vascular targets in pericytes
aminopeptidases APA and APN, NG2 proteoglycan, PDGFRs
Vascular targets in tumour cells
VEGF and VEGFR receptors, αvβ3 and αvβ5 integrins, MMP-2, MMP-9, EGFR
Define gene therapy
Delivering a therapeutic gene to replace and correct an abnormal gene
Examples of viral vectors?
retroviruses/lentiviruses- RNA, adenoviruses (Ad)- dsDNA, adeno-associated viruses (AAV)- ssDNA
Examples of non-viral vectors?
- Lipoproteins (w/ aqueous core)
- Cation polymers (+ve region binds to -ve tumour cells)
How to make a vector?
- Replace wild-type gene with the therapeutic gene
- Use a gene promoter e.g. CMV promoter (before the therapeutic gene)
- Use a PolyA sequence to stop transcription (after the therapeutic gene)
Problems with eukaryotic viral vectors?
- Undesired uptake by liver
- Uptake by reticuloendothelial system (RES)
- Tropism for normal tissues
- Low penetrance for tumour tissues
- Presence of antiviral neutralising antibodies
Advantages of Bacteriophage therapies?
- Safe (if no bacteria left, cleared within 3 days)
- Targeted (ligand-directed targeting)
- Cost-effective production at high titres
- No need to ablate for any tropism
Types of Bacteriophage?
- Tailed: bacteriophage lambda (dsDNA)
- Filamentous: bacteriophage M13 (ssDNA)
Describe bacteriophage entry
- Phage binds to pilus
- Phage DNA inserted into cell cytoplasm
Advantages of RGD-AAVP?
- Specific for brain tumours (binds to αv-integrin receptor)
- IV delivery
- Easily crosses BBB
- Cheap to produce
Typical medulloblastoma patient?
Most common brain tumour in children
high survival and high morbidity
Medulloblastoma response to TMZ
It is resistant
Treatment approaches for medulloblastoma?
- Short hairpin RNA (shRNA) to neutralise mRNA and block expression -> kills 40% of tumour cells
- Cilengitide (blocks integrins) -> small effect to block tumour growth
- Phage to deliver shRNA and block mTOR pathway and THEN give TMZ (as resistance is removed)
Typical diffuse intrinsic pontine glioma patient (DIPG)
Young children
What is chemovirotherapy?
Combining chemo-radiotherapy with gene therapy (e.g. AAVP+TMZ)
Non-targeted AAVP without RGD: ___
TMZ: ___
RGD-AAVP and HSVTk: ___
RGD-AAVP with TMZ: ___
Non-targed AAVP without RGD: no effect
TMZ: small effect
RGD-AAVP and HSVTk: tumour shrinks slightly
RGD-AAVP with TMZ: 100% tumour cells eliminated
