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Newer cancer therapies
Immunotherapy
Angiotherapy
Gene therapy
Immunotherapy
Immunotherapy
Immunotherapy

Non-specific immunotherapy
BCG
 Cytokines
 Cell therapy


Specific immunotherapy

adoptive
Antibody therapy
 Adoptive transfer of T cells


Vaccination
Tumour-based vaccines
 Virus-based vaccines
 Peptide-based vaccines
 others

Immunotherapy
Immunotherapy
Immunotherapy
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
BLOOD FLOW
Before treatment
after treatment
MMPIs

Disappointing results with matrix
metalloproteinase inhibitors

Poor survival rate in phase III clinical trials
against renal cell carcinoma
Newer cancer therapies
Gene therapy
Severe Combined Immunodeficiency Disease (SCID)
Gene therapy
Antisense therapy
(suppress gene expression)
Gene augmentation
(supplement defective gene)
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
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
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.
3 challenges in gene therapy
delivery
delivery
delivery
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
Vectors
Carrier molecules designed
specifically to enter cells & deposit
therapeutic genes
Vectors can be viral or non-viral
METHODS OF VECTOR DELIVERY
Viral vector strategy
Replication & virulence genes can be
substituted with therapeutic genes
Retroviral vectors
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
Adenoviral vectors
do not insert into
genome
temporary
lack of specificity
strong immune
response
Adeno-associated viral vectors
Integrate
into
genome but
small in
size
Nature Reviews Genetics
1; 91-99 (2000);
Non-viral Vectors
Advantages
non-toxic
no immune response
Tumour-suppressor gene delivery
Nature Reviews
Cancer (2001)
Vol 1; 130-141
Delivery of agents that block
oncogene expression
Nature
Reviews
Cancer
(2001)
Vol 1; 130141
Suicide gene delivery
Nature Reviews Cancer (2001) Vol 1; 130-141
Conditionally replicating viruses
Non-viral Vectors
liposomes (lipoplexes)
Non-viral Vectors
amino acid polymers: cationic polymers
e.g. B-cyclodextrins
Non-viral Vectors
Gene gun
naked DNA
artificial human chromosomes
Successes

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)

CML results through a chromosomal rearrangement that fuses two genes
together. This produces an oncogene that encodes an enzyme, a form of
tyrosine kinase known as BCR-ABL. Unchecked production of that enzyme
leads to excessive levels of white blood cells in the blood and bone marrow.
that disrupts the normal production of white blood cells.

Gleevec works specifically to block the activity of that form of tyrosine
kinase.