Newer cancer therapiesNewer cancer therapies

ImmunotherapyImmunotherapyAngiotherapy Angiotherapy Gene therapyGene therapy

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy Non-specific immunotherapyNon-specific immunotherapy

BCG BCG CytokinesCytokines Cell therapyCell therapy

Specific immunotherapySpecific immunotherapy adoptive adoptive

Antibody therapyAntibody therapy Adoptive transfer of T cellsAdoptive transfer of T cells

VaccinationVaccination Tumour-based vaccinesTumour-based vaccines Virus-based vaccinesVirus-based vaccines Peptide-based vaccinesPeptide-based vaccines othersothers

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy

AngiotherapyAngiotherapy

Key differences in tumour Key differences in tumour vasculaturevasculature

Different flow Different flow characteristics / characteristics / blood volumeblood volume

Microvasculature Microvasculature permeabilitypermeability

Increased Increased fractional fractional volume of volume of extravascular, extravascular, extracellular extracellular spacespace

Angiogenesis-overviewAngiogenesis-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

MMPIsMMPIs

Disappointing results with matrix Disappointing results with matrix metalloproteinase inhibitors metalloproteinase inhibitors

Poor survival rate in phase III clinical trials Poor survival rate in phase III clinical trials against renal cell carcinomaagainst renal cell carcinoma

Newer cancer therapiesNewer cancer therapiesGene therapyGene therapy

Severe Combined Immunodeficiency Disease (SCID)

Antisense therapy Antisense therapy (suppress gene expression)(suppress gene expression)

Gene augmentation Gene augmentation (supplement defective gene)(supplement defective gene)

Gene therapyGene therapy

Antisense therapyAntisense therapycompensates for genetic compensates for genetic

mutations that produce mutations that produce destructive proteinsdestructive proteins

Main strategies involved areMain strategies involved are

1) short stretches of synthetic 1) short stretches of synthetic DNA that target the mRNA DNA that target the mRNA transcripts of abnormal transcripts of abnormal proteins preventing its proteins preventing its translation ORtranslation OR

small RNA molecules small RNA molecules (siRNA) used to degrade (siRNA) used to degrade aberrant RNA transcriptsaberrant RNA transcripts

Antisense therapyAntisense therapy

2) provide a gene for a 2) provide a gene for a protein (intracellular protein (intracellular antibody) that can antibody) that can block the activity of the block the activity of the mutant proteinmutant protein

Tumor necrosis therapy utilizes monoclonal antibodies targeting intracellular tumor antigens on necrotic (dead) tissue. This method overcomes some of the limitations of current antibody-based therapeutic approaches

3)3) design hybrids of design hybrids of DNA / RNA that DNA / RNA that might direct repair of might direct repair of the mutant gene the mutant gene

Gene augmentationGene augmentationmost therapies simply add a useful gene into a most therapies simply add a useful gene into a

selected cell type to compensate for the missing or selected cell type to compensate for the missing or flawed version or even instil an entirely new flawed version or even instil an entirely new version. version.

Direct approach Direct approach

inducing cancer cells to make a protein that will kill inducing cancer cells to make a protein that will kill the cell. the cell.

Indirect approach Indirect approach

stimulating an immune response against selected stimulating an immune response against selected cells or eliminating the blood supply. cells or eliminating the blood supply.

deliverydelivery

3 challenges in gene therapy3 challenges in gene therapy

deliverydelivery deliverydelivery

1)1) Package the genePackage the gene2)2) Protect the geneProtect the gene3)3) deliver to the nucleus and release deliver to the nucleus and release

in an active formin an active form

Vectors ‘Trojan horses’ that sneak the gene into the cell

Carrier molecules designed Carrier molecules designed specifically to enter cells & deposit specifically to enter cells & deposit

therapeutic genestherapeutic genes

Vectors can be viral or non-viral Vectors can be viral or non-viral

VectorsVectors

METHODS OF VECTOR DELIVERYMETHODS OF VECTOR DELIVERY

Viral vector strategyViral vector strategyReplication & virulence genes can be Replication & virulence genes can be

substituted with therapeutic genessubstituted with therapeutic genes

designed to enter cell and deposit genesdesigned to enter cell and deposit genes

Problems Problems of retroviral therapy includeof retroviral therapy include

Lack of cell specificity:Lack of cell specificity: Promiscuous: depositing genes into Promiscuous: depositing genes into several cell types resulting in reduced several cell types resulting in reduced target efficiency and unwanted target efficiency and unwanted physiological effectsphysiological effects

Random splicing into host DNARandom splicing into host DNA resulting in normal gene disruption resulting in normal gene disruption and/or alteration in gene function and/or alteration in gene function

Retroviral vectorsRetroviral vectors

Adenoviral vectorsAdenoviral vectors

do not insert into genome

temporary

lack of specificity

strong immune response

Adeno-associated viral vectorsAdeno-associated viral vectors

Nature Reviews Genetics 1; 91-99 (2000);

Integrate into genome but small in size

AdvantagesAdvantages

non-toxicnon-toxic

no immune responseno immune response

Non-viral VectorsNon-viral Vectors

Tumour-suppressor gene deliveryTumour-suppressor gene delivery

Nature Reviews Cancer (2001) Vol 1; 130-141

Delivery of agents that block Delivery of agents that block oncogene expressiononcogene expression

Nature Reviews Cancer (2001) Vol 1; 130-141

Suicide gene deliverySuicide gene delivery

Nature Reviews Cancer (2001) Vol 1; 130-141

Conditionally replicating virusesConditionally replicating viruses

Non-viral VectorsNon-viral Vectors

liposomes (lipoplexes)liposomes (lipoplexes)

amino acid polymers: cationic polymers amino acid polymers: cationic polymers

e.g. B-cyclodextrinse.g. B-cyclodextrins

Non-viral VectorsNon-viral Vectors

naked DNA naked DNA

artificial human chromosomes artificial human chromosomes

Non-viral VectorsNon-viral Vectors Gene gun

SuccessesSuccesses Cancer and the p53 gene. Researchers used a virus to carry a normal

copy of the p53 gene into the abdominal and pelvic areas of women with advanced ovarian cancer. Seven of 25 women tested in California and Iowa survived more than 2 years after the therapy, despite having a terminal diagnosis.

Cancer and enzyme therapy. This type of therapy targets enzymes, or proteins, that are made by abnormal genes. Example: Gleevec, a new drug, targets an abnormal protein produced by a cancer-causing gene. The abnormal protein is necessary for some types of cancer to survive and reproduce. Gleevec blocks the action of the protein. Gleevec has been successful in chronic myeloid leukemia and in gastrointestinal stromal tumors. It is being tested in other types of cancer.

Cancer and other therapies. Advances in identifying genes have helped researchers to target other therapies. Example: Herceptin targets the HER-2 gene. In 25%-35% of breast cancers, HER-2 produces too many copies of itself, causing breast cancer cells to reproduce out of control and spread throughout the body. Herceptin blocks excess HER-2 by binding to growth receptors on the surface of the cell, causing tumors to shrink.

Gleevec for chronic myeloid leukaemia (CML)Gleevec for chronic myeloid leukaemia (CML) CML results through a chromosomal rearrangement that fuses two genes CML results through a chromosomal rearrangement that fuses two genes

together. This produces an oncogene that encodes an enzyme, a form of together. This produces an oncogene that encodes an enzyme, a form of tyrosine kinase known as tyrosine kinase known as BCR-ABL.BCR-ABL. Unchecked production of that enzyme Unchecked production of that enzyme leads to excessive levels of white blood cells in the blood and bone marrow. leads to excessive levels of white blood cells in the blood and bone marrow. that disrupts the normal production of white blood cells. that disrupts the normal production of white blood cells.

Gleevec works specifically to block the activity of that form of tyrosine Gleevec works specifically to block the activity of that form of tyrosine kinase. kinase.