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Cancer therapy
IJsbrand Kramer i.kramer_at_iecb.u-bordeaux.fr
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In this lecture we will treat - The principles
of cancer chemotherapy - The principles of
clinical trials - The development of novel
anti-cancer drugs - the Abl tyrosine kinase
inhibitor Gleevec - the HER2 receptor-inhibitor
Herceptin Fab
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Cancer can be treated in four ways 1) surgical
excision, 2) irradiation, 3) chemotherapy and
4) biological response modification. Cancer
chemotherapy takes central stage in the cure of
cancer and for certain tumours, high survival
rates have been achieved.
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The first anticancer drugs, the nitrogen
mustards, were initially developed as toxic gases
during the first World War. Victims of gas
attacks were found to have very low white blood
cell counts. It was then reasoned that these
compounds could be developed as anticancer drugs
for the treatment of leukaemias. These compounds
are now known as the alkylating agents and are
still an essential ingredient of chemotherapy
regimes.
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Anticancer drugs inhibit cell proliferation and
although effective in combating cancer, they
cause proliferation arrest in both disordered-
and ordered-cells! Their mode of action is not
based on a clear exploitable difference.
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The exploitable difference may reside in the
recovery phase after the treatment We may
define the exploitable difference for cancer
therapy as follows a reduced capacity of the
cancer cell to repair the damage induced by
chemotherapy agents. Because of this, cancer
cells pass on to their progenitors an increasing
number of defects (mutations) that in the end
prove to be lethal.
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Anti-metabolites
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Anti-metabolites
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Anti-metabolites
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Anti-metabolites
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Anti-metabolites
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Alkylating agents
Mustard gas (yperite)
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Alkylating agents
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Alkylating agents
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Platinum analogues
Cisplatin (red) linking two nucleotides (blue)
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Platinum analogues
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Cytotoxic antibiotics
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Inhibitors of microtubule polymerization or
depolymerization
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• Development of new anticancer drugs
• New targets and how to test their clinical
  efficacy?
• Principles of clinical trials
• The development of Gleevec
• The development of Herceptin Fab

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Principals of Clinical trials
1 dose response test 2 randomized 3 double
blind 4 inclusion of control Control -
application of placebo (no drug but this may not
always be possible for ethical reasons (disabling
or lethal disease)) - application of existing
treatment (the disadvantage of such an approach
is that you have no direct evidence of the
therapeutic action of the drugs)
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Principals of Clinical trials
A Phase I Study Phase I studies are primarily
concerned with assessing the drug's safety. This
initial phase of testing in humans is done in a
small number of healthy volunteers (20 to 100),
who are usually paid for participating in the
study. The study is designed to determine what
happens to the drug in the human body--how it is
absorbed, metabolized, and excreted. A phase I
study will investigate adverse effects that
occur as dosage levels are increased. This
initial phase of testing typically takes several
months. About 70 percent of experimental drugs
pass this initial phase of testing. NB For
cancer drugs this phase already contains selected
patients that respond badly to the standard
treatment and are in an advanced state of the
disease.
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Principals of Clinical trials
A Phase Two Study Once a drug has been shown
to be safe and a dose response curve has been
established, it must be tested for efficacy in a
larger number of people. This second phase of
testing may last from several months to two
years, and involve up to several hundred
patients. Randomized, double blind and with
control. NB For cancer therapy a different
approach applies the trial is not random, the
patients are selected by criteria such as
severity of disease and unresponsiveness to
standard treatment. This study will provide the
pharmaceutical company and the FDA comparative
information about the relative safety of the new
drug, and its effectiveness (therapeutic index).
Only about one-third of experimental drugs
successfully complete both phase I and phase II
studies.
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Principals of Clinical trials
A Phase Three Study In a phase III study, a
drug is tested in several hundred to several
thousand patients. This large-scale testing
provides the pharmaceutical company and the FDA
with a more thorough understanding of the drug's
effectiveness, benefits, and the range of
possible adverse reactions. Most phase III
studies are randomized and blinded trials.
Phase III studies typically last several years.
Seventy to 90 percent of drugs that enter phase
III studies successfully complete this phase of
testing. Once a phase III study is successfully
completed, a pharmaceutical company can request
FDA approval for marketing the drug.
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1. Gleevec and the treatment of Chronic
myelogenous lymphoma (CML)
Chronic myelogenous leukemia (leukemia meaning
white blood ) results from an acquired (not
inherited) chromosomal translocation between
chromosome 9 and 22, resulting in the formation
of a large and very small chromosome, called the
Philadelphia chromosome. What produces this
translocation is not yet understood. The
translocation confers a growth and survival
advantage on the stem cell and this leads to a
massive increase of white blood cells. Unlike
acute myelogenous leukemia, chronic myelogenous
leukemia permits the development of mature white
blood cells and platelets that generally can
function normally. This important distinction
from acute leukemia accounts for the less severe
early course of the disease.
Also known as chronic granulocytic, chronic
myelocytic or chronic myeloid leukemia
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Chronic myelogenous lymphoma (CML)
The disease typically begins with a chronic phase
and progresses to blast crisis over a period of
years. At the time of blast crisis, CML cells
often have acquired secondary genetic
abnormalities in addition to Brc-Abl. Because
all patients express the Bcr-Abl protein, in both
chronic and acute phase, it represents an ideal
target for drug therapy
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The incidence of CML increases with age a good
illustration of cancer being an age-related
disease
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60
80
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age (years)
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Chronic myelogenous lymphoma (CML) symptoms
Carriers of the disease tire more easily and
may feel short of breath when physically active.
They may have a pale complexion from anemia.
Discomfort on the left side of the abdomen from
an enlarged spleen may be present. They may
experience excessive sweating at night, weight
loss, and inability to tolerate warm
temperatures. Increasingly, the disease is
discovered during the course of a periodic
medical examination.
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Philadelphia chromosome
So named because this chromosomal translocation
(Ph1) was discovered in Philadelphia in 1960.
Bcr stands for breakpoint cluster region, a
site in chromosome 22 which is frequently
involved in translocations Abl stands for
Abelson (gene product homologous to oncogenic
virus carried by the Abelson leukemia virus v-Abl)
Bcr Abl
Bcr
Abl
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Fluorescence in situ hybridization, often
referred to as FISH, is a method to identify
cells with the 922 translocation characteristic
of CML
Abl Bcr Abl-Bcr
Abl Bcr
When Abl and Bcr are fused, the red and green
fluorescent probes superimpose and give a yellow
signal (so one set of chromosomes is still intact)
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The Philadelphia chromosome harbours a fusion
gene called Bcr-Abl
The translocation produces a fusion protein
Abl-Bcr which is associated with Chronic
Myelogenous Leukemia
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Abl has different activation states, from
inactive (a) to intermediate states (c-f) and
fully active (b). Bcr-Abl cannot return to an
inactive state (g) and is said to be constitutive
active.
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Treatment of Chronic Myelogenous Leukemia
Stem Cell Transplantation is applied when all
fails (with matching HLA donor)
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Treatment of Chronic Myelogenous Leukemia
Interferon-a has been an important addition to
the treatment of CML. In 2001, the Food and
Drug Administration approved imatinib mesylate
(Gleevec in the USA, and Glivec elsewhere) for
patients resistant or unable to tolerate
interferon-a. The drug has been very effective
in this setting and may become the most common
first choice for treatment in the future.
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In search for an inhibitor of Abl
Signal Transduction Inhibitor STI-571
4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-4-METHYL-3-(
4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL-BENZA
MIDE (Novartis) Also known as Gleevec, Glivec or
imatinib
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Specificity of inhibition

• STI-571 inhibits (until today)
• - Bcr-Abl
• PDGF-R
• c-kit (receptor for the Stem Cell Factor)

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FDA approval (in 2002) for treatment of newly
diagnosed patients with Gleevec The food and
drug administration (FDA) approved Gleevec as a
first-line therapy for CML based on the data
obtained from a 12 month international randomized
trial of Interferon-a versus Gleevec (STI-571).
This phase III trial involved 553 patients that
were given Gleevec and 553 that were given a
standard therapy of Interferon-a and cytarabine
(anti-metabolite). The patients treated with
Gleevec after one year had significantly fewer
cancerous cells in their blood and bone marrow.
The rate of progression was also decreased. The
lenght of the follow up is still too short to
measure long term clinical benefits (generally
presented 5 years survival rates)
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Adverse effects of Gleevec treatment

• Most of the adverse affects can be managed
  without
• stopping therapy. Among others they are
• - Fluid retention
• - Nausea
• - Vomiting
• - Muscle cramps
• - Diarrhoea
• Rashes
• and (very rarely)
• -heart failure (late onset adverse effect)

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Timeline of major CML discoveries and drug
development
A-MuLV Abelson murine leukemia virus GAG-Abl
fusion product of viral glycosylated antigen
with the Abl tyrosine kinase
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2. Herceptin Fab and the treatment of Her2-driven
metastatic breast cancer - The human epidermal
growht factor receptor-2 (ERBB2, also known as
neu or Her2) is amplified in 30 of breast
cancers. - Amplification of ERBB2 is associated
with an aggressive form of the disease
(metastaticwith shortened overall survival
time. - In vitro experiments have demonstrated a
direct role of ERBB2 in the pathogenesis of this
cancer
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ERBB2 is a member of the family of EGF receptors
but, until today, lacks a high affinity ligand.
Amplification of ERBB2 causes cell transformation
without the apparent involvement of a ligand.
This may be explained by its open
conformation (unlike ERBB1, 3 or 4)
dimerization arm
ERBB2 extracellular domain
ERBB2 extracellular domain antibody
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Example of a clinical trial protocol in which
Herceptin (trastuzumab) has been tested
treatment
control
treatment
control
Trastuzumab 4mg/kg (0.22 gr/person), anti-HER2
Fab fragment Anthracycline is doxorubucin,
inhibitor of DNA polymerase Cyclophosphamide is a
alkylating agent that binds DNA and inhibits DNA
polymerase Paclitaxel is taxol, inhibitor of
microtubule depolymerization
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Survival rates of metastatic ERBB2-positive
breast cancer
The use of trastuzumab (mAb) increases the
percentage of survival by 10 after two years
(red lines).