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Cancer therapy. IJsbrand Kramer i.kramer@iecb.u-bordeaux.fr. 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

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slide1

Cancer therapy

IJsbrand Kramer

i.kramer@iecb.u-bordeaux.fr

slide2

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

slide3

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.

slide4

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 leukaemia’s.

These compounds are now known as the alkylating agents and are still an essential ingredient of chemotherapy regimes.

slide5

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.

slide6

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.

slide13

Alkylating agents

Mustard gas

(yperite)

slide16

Platinum analogues

Cisplatin (red) linking two

nucleotides (blue)

slide25

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
slide26

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)

slide27

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.

slide28

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.

slide29

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.

slide30

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

slide31

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

slide32

The incidence of CML increases with age: a good illustration of cancer being an age-related disease

20

40

60

80

age (years)

slide33

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.

slide34

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

slide35

Fluorescence in situ hybridization, often referred to as FISH, is a method to identify cells with the 9;22 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)

slide36

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

slide37

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.

slide38

Treatment of Chronic Myelogenous Leukemia

Stem Cell Transplantation is applied when all fails (with matching HLA donor)

slide39

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.

slide40

In search for an inhibitor of Abl

Signal Transduction Inhibitor STI-5714-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE (Novartis)

Also known as Gleevec, Glivec or imatinib

slide41

Specificity of inhibition

  • STI-571 inhibits (until today)
  • - Bcr-Abl
  • PDGF-R
  • c-kit (receptor for the Stem Cell Factor)
slide42

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)

slide43

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)
slide44

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

slide45

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

slide46

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

slide48

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

slide49

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).