Newer cancer therapies immunotherapy angiotherapy gene therapy

Angiotherapy

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

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

Before treatment after treatment BLOOD FLOW

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

Newer cancer therapies gene therapy

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

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

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

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.

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

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

METHODS OF VECTOR DELIVERY

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

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

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

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

Conditionally replicating viruses

Advantages non-toxic no immune response Non-viral Vectors

liposomes (lipoplexes)

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

naked DNA artificial human chromosomes Non-viral Vectors Gene gun

Tumour-suppressor gene delivery Nature Reviews Cancer (2001) Vol 1;

Delivery of agents that block oncogene expression Nature Reviews Cancer (2001) Vol 1;

Suicide gene delivery Nature Reviews Cancer (2001) Vol 1;