1. Newer cancer therapies immunotherapy angiotherapy gene therapy

2. Angiotherapy

3. Key differences in tumour vasculature Different flow characteristics / blood volume Microvasculature permeability Increased fractional volume of extravascular, extracellular space

4. Angiogenesis-overview Balance between inhibitory factors (endostatin) and angiogenic factors (VEGF, bFGF) angiogenic factors stimulate MMPs and plasminogen activators Degradation of basement membrane Invasion and differentiation of endothelial cells in surrounding tissues

6. Before treatment after treatment BLOOD FLOW

7. MMPIs Disappointing results with matrix metalloproteinase inhibitors Disappointing results with matrix metalloproteinase inhibitors Poor survival rate in phase III clinical trials against renal cell carcinoma Poor survival rate in phase III clinical trials against renal cell carcinoma

8. Newer cancer therapies gene therapy

9. Antisense therapy (suppress gene expression) Gene augmentation (supplement defective gene) Gene therapy

10. Antisense therapy compensates for genetic mutations that produce destructive proteins Main strategies involved are 1) short stretches of synthetic DNA that target the mRNA transcripts of abnormal proteins preventing its translation OR small RNA molecules (siRNA) used to degrade aberrant RNA transcripts

11. Antisense therapy 2) provide a gene for a protein (intracellular antibody) that can block the activity of the mutant protein 3) design hybrids of DNA / RNA that might direct repair of the mutant gene

12. Gene augmentation most therapies simply add a useful gene into a selected cell type to compensate for the missing or flawed version or even instil an entirely new version. Direct approach inducing cancer cells to make a protein that will kill the cell. Indirect approach stimulating an immune response against selected cells or eliminating the blood supply.

13. delivery 3 challenges in gene therapy deliverydelivery 1) Package the gene 2) Protect the gene 3) deliver to the nucleus and release in an active form Vectors ‘Trojan horses’ that sneak the gene into the cell

14. Carrier molecules designed specifically to enter cells & deposit therapeutic genes Vectors can be viral or non-viral Vectors

15. METHODS OF VECTOR DELIVERY

16. Viral vector strategy Replication & virulence genes can be substituted with therapeutic genes

17. designed to enter cell and deposit genes Problems of retroviral therapy include Lack of cell specificity: Promiscuous: depositing genes into several cell types resulting in reduced target efficiency and unwanted physiological effects Random splicing into host DNA resulting in normal gene disruption and/or alteration in gene function Retroviral vectors

18. Adenoviral vectors do not insert into genome temporary lack of specificity strong immune response

19. Adeno-associated viral vectors Nature Reviews Genetics 1; 91-99 (2000); Integrate into genome but small in size

20. Conditionally replicating viruses

21. Advantages non-toxic no immune response Non-viral Vectors

22. liposomes (lipoplexes)

23. amino acid polymers: cationic polymers e.g. B-cyclodextrins Non-viral Vectors

24. naked DNA artificial human chromosomes Non-viral Vectors Gene gun

25. Tumour-suppressor gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141

26. Delivery of agents that block oncogene expression Nature Reviews Cancer (2001) Vol 1; 130- 141

27. Suicide gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141