Therapeutic Targeting of Brain Tumours

Question 1

Efficacy of systemic temozolomide-activated

phage-targeted gene therapy in human glioblastoma Justyna Magdalena Przystal

Answer 1

• Glioblastoma is one of the most lethal primary intracranial malignant neoplasm
• Combined gene therapy with TMZ chemotherapy and chemovirotherapy
• TMZ treatment of human glioblastoma cell lines increased expression of Grp78, stimulating RGD4C gene expression. Also amplified destruction of GBM cells.
• Combination therapy has significant potential - as the phages enhance TMZ chemotherapy
• Strong expression of a integrin in the tumours but not healthy brain, so can be targeted.
• Cucurmin can help treatment of glioblastoma

Question 2

List challenges for brain tumour treatment

Answer 2

• Blood brain barrier
• Resistance (due to heterogeneity)
• Heterogeneity
• Diffusing nature of some brain tumours, with inability to remove large amounts of tissue
• Invasiveness of local delivery into the brain
• Lack of efficacy through the systemic circulation (due to the blood brain barrier)
• Limitations attributable to the medicine itself

Question 3

Describe the role of BBB in tumour disruption

Answer 3

• Chemotherapy drugs need to cross the blood brain barrier to access the tumour
• Then have to cross the pericytes and additional layer of astrocytes
• Only lipophilic molecules can cross the BBB
• Doxorubicin accumulates poorly in the brain when given systematically (high molecular weight and low lipophilicy)
• P-glycoprotein is present which has an efflux pump to pump anticancer drugs out the cells
• Temozolomide is most used in the brain, as it can cross the blood brain barrier

Question 4

Describe methods to deliver chemotherapy drugs to the brain

Answer 4

• Osmotic opening of the BBB using arabinose or mannitol
• Local delivery (convection enhanced delivery via catheter, polymeric vesicles via gliadel)
• Targeted drug delivery to increase efficacy and safety, allowing delivery of a drug to a specific part of the body + non invasive and safer (polymers, liposomes, viruses)

Question 5

Why is the vasculature of a solid tumour an attractive target for intervention?

Answer 5

1. The Tumour endothelium expresses specific markers, that are absent or barely
   detectable in the normal quiescent blood vessels (post codes, vascular targets).
2. Endothelial cells lining the blood vessels are directly accessible to drugs via the systemic circulation.
3. It is estimated that up of 100 tumour cells are sustained by a single endothelial cell.
4. Endothelial cells are genetically more stable and are therefore unlikely to acquire resistance to therapy.

Question 6

List potential limitations of antiangiogenic agents and other therapeutic medicine

Answer 6

i) Short half-lives
ii) Rapid renal clearance
iii) High chance of non-specific accumulation
iv) Inefficient accumulation at the diseased site
v) Severe side effects at high doses
vi) Tumour resistance due to GBM heterogeneity

Question 7

List viral vectors

Answer 7

• Reteroviruses and lentiviruses
• Adenoviruses
• Adeno-associated viruses
• Herpes simplex virus

Question 8

List advantages of bacteriophages as delivery systems

Answer 8

• Safe, administered to humans in antibiotic therapy
• No need to ablate any native tropism
• Ligand directed targeting is well established
• Cost effective production in bacteria and at high titers