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Title: Anti-Angiogenic Cancer Therapies


1
Anti-Angiogenic Cancer Therapies
  • Tangela S. Feemster
  • Tuesday, March 27, 2007
  • Dr. Buynak
  • Medicinal Chemistry

2
Definition of Angiogenic Therapy
  • A new form of cancer treatment using drugs called
    'angiogenesis inhibitors' that specifically halt
    new blood vessel growth and starve a tumor by
    cutting off its blood supply.
  • A substance in the body called Vascular
    Endothelial Growth Factor (VEGF) is responsible
    for the growth of new blood vessels. It promotes
    this growth by stimulating the endothelial cells,
    which form the walls of the vessels and transport
    nutrients and oxygen to the tissues.
  • Anti-Angiogenic drugs prevent the VEGF from
    binding with the receptors on the surface of the
    endothelial cells.

3
Three Major Types of Anti-angiogenic Therapies
for Cancer
  1. Drugs that stop new blood vessels from sprouting
    (true angiogenesis inhibitors)
  2. Drugs that attack a tumor's established blood
    supply (vascular targeting agents)
  3. Drugs that attack both the cancer cells as well
    as blood vessel cells (the double-barreled
    approach).

4
To date more than 300 angiogenesis inhibitor
molecules have been discoveredSome angiogenesis
inhibitors are naturally present in the human
body because healthy tissues appear to resist
cancer growth by containing these anti-angiogenic
compounds.
List of 32 Known Angiogenesis Inhibitors in the Body List of 32 Known Angiogenesis Inhibitors in the Body
Angiostatin (plasminogen fragment) Metalloproteinase inhibitors (TIMPs)
Anti-angiogenic antithrombin III (aaATIII) Pigment epithelial-derived factor (PEDF)
Canstatin Placental ribonuclease inhibitor
Cartilage-derived inhibitor (CDI) Plasminogen activator inhibitor
CD59 complement fragment Platelet factor-4 (PF4)
Endostatin (collagen XVIII fragment) Prolactin 16kD fragment
Fibronectin fragment Proliferin-related protein
Gro-beta Retinoids
Heparinases Tetrahydroco
Heparin hexasaccharide fragment rtisol-S
Human chorionic gonadotropin (hCG) Thrombospondin-1
Interferon alpha/beta/gamma Transforming growth factor-beta
Interferon inducible protein (IP-10) Tumistatin
Interleukin-12 (IL-12) Vasculostatin
Kringle 5 (plasminogen fragment) Vasostatin (calreticulin fragment)
2-Methoxyestradiol (2-d) Angioarrestin
5
Angiogenesis Inhibitors
  • Other angiogenesis inhibitors have been found in
    nature - in green tea, soy products, fungi,
    mushrooms, Chinese cabbage, tree bark, shark
    tissues, snake venom, red wine, and many other
    substances.
  • Still other angiogenesis inhibitors have been
    manufactured synthetically in the laboratory.
  • Some FDA-approved medicines have also been
    "re-discovered" to have anti-angiogenic
    properties.

6
Angiogenic Inhibitors
  • Currently, a number of clinical trials in
    progress are combining anti-angiogenic therapy
    with cytotoxic chemotherapy or radiation, as a
    way to maximize the anti-tumor treatment in human
    cancer patients sponsored by biotechnology and
    pharmaceutical companies, medical centers and by
    the U.S. National Cancer Institute. These
    clinical trials are taking place in the United
    States, Canada, Australia, and throughout Europe.

7
Anti-Angiogenic Drugs in Clinical Trial for
Cancer
A6Alpha5Beta1 Integrin AntibodyABT-510ActimidAngiocolAngiostatinAngiozymeAplidineAptosynATN-161Avastin (bevacizumab)AVE8062ABenefinBMS275291CarboxymidotriazoleCC4047CC7085CDC801Celebrex (Celecoxib)CEP-7055CGP-41251/PKC412 Cilengitide Combretastatin A4PCP-547, 632CP-564, 959DexrazoxaneDidemnin BDMXAAEMD 121974EndostatinFlavopiridolGBC-100Genistein Concentrated PolysaccharideGreen Tea ExtractInterleukin-12INGN 201Interferon alfaIressaLY317615Mab huJ591-DOTA-90 Yttrium (90Y)Medi-522Metaret (suramin)Metastat (Col-3) NeovastatNM-3NPe6OctreotideOltiprazPaclitaxelPanzem (2ME2)PenicillaminePI-88PSKPTK787/ZK222584RevimidRo317453SqualamineSU11248SU6668TemptostatinTetrathiomolThalidomideUCN-01VEGF Trap ZD6126ZD647
8
Understanding Angiogenesis
  • Angiogenesis is defined as the growth of blood
    vessels and is an important natural process used
    by the body for reproduction and for healing
    injured tissues
  • Blood vessels bring oxygen and nutrients via the
    circulation to nourish all tissues in the body
  • The cells comprising blood vessels are called
    endothelial cells
  • The endothelial cells of a blood vessel also
    produce molecules that support the growth of
    tissues
  • Cancer cells take over the body's control of
    angiogenesis in order to recruit their own
    private blood supply

9
Historical Highlights of the Anti-Angiogenesis
Field
  • 1787 - British surgeon Dr. John Hunter first uses
    the term 'angiogenesis' (new blood vessel
    growth) to describe blood vessels growing in
    the reindeer antler
  • 1971 - Surgeon Dr. Judah Folkman hypothesizes
    that tumor growth is dependent upon
    angiogenesis. His theory, published in the New
    England Journal of Medicine, and is initially
    regarded as heresy by leading physician and
    scientists.
  • 1975 - The first angiogenesis inhibitor is
    discovered in cartilage by Dr. Henry Brem and
    Dr. Judah Folkman.
  • 1984 - The first angiogenic factor (basic
    fibroblast growth factor, bFGF) is purified by
    Yuen Shing and Michael Klagsbrun at Harvard
    Medical School.
  • 1989 - One of the most important angiogenic
    factors, vascular endothelial growth factor
    (VEGF), is discovered by Dr. Napoleone Ferrara
    and by Dr. Jean Plouet. It turns out to be
    identical to a molecule called Vascular
    Permeability Factor (VPF) discovered in 1983
    by Dr. Harold Dvorak.

10
Historical Highlights of the Anti-Angiogenesis
Field
  • 1997 - Dr. Michael O'Reilly publishes research
    finding in the journal Nature showing complete
    regression of cancerous tumors following
    repeated cycles of anti-angiogenic therapy
    using angiostatin and endostatin
  • 1999 - Massive wave of anti-angiogenic drugs in
    clinical trials 46 anti- angiogenic drugs for
    cancer patients 5 drugs for macular
    degeneration 1 drug for diabetic retinopathy
    4 drugs for psoriasis.
  • 1999 - Dr. Richard Klausner, Director of the U.S.
    National Cancer Institute designates the
    development of anti-angiogenic therapies for
    cancer as a national priority.
  • 2003 - The monoclonal antibody drug Avastin
    (Bevacizumab) becomes the first anti-angiogenic
    drug shown in large-scale clinical trials
    inhibiting tumor blood vessel growth can
    prolong survival in cancer patients.

11
Specific Angiogenic Inhibitors
  • Angiostatin
  • Avastin (Bevacizumab)
  • Celebrex (Celecoxib)
  • Endostatin
  • Metaret (Suramin)
  • Thalidomide

12
Angiostatin
  • Naturally occurring protein found in several
    animal species, including humans.
  • It is an endogenous angiogenesis inhibitor
  • Angiostatin is produced by autoproteolytic
    cleavage of plasminogen,
  • Can be cleaved from plasminogen by different
    metalloproteinases (MMPs), elastase,
    prostata-specific antigen (PSA), 13 KD serine
    protease, or 24KD endopeptidase.

13
Angiostatin
  • It is a 57 kDa fragment of a larger protein,
    Plasmin (itself a fragment of plasminogen)
  • Encloses three to five contiguous Kringle
    modules.
  • Each Kringle module contains two small beta
    sheets and three disulfide bonds.
  • Considerable uncertainty on its mechanism of
    action, but it seems to involve the inhibition of
    endothelial cell migration, proliferation and
    induction of apoptosis.

14
Avastin
  • Avastin is a humanized monoclonal antibody (MAb)
    that targets vascular endothelial growth factor
    (VEGF)
  • Causes regression of tumor vasculature
  • Reduces intra-tumor pressure, thereby improving
    the delivery of cytotoxic agents to the tumor
  • Also inhibits new tumor blood vessel formation,
    restricting tumor growth.
  • The first anti-angiogenic agent with demonstrated
    anticancer benefit in phase III trials.
  • Avastin-VEGF Animation

15
Celecoxib
  • Is one of the rediscovered drugs
  • It is better known as Celebrex, a non-steroidal,
    anti-inflammatory drug
  • Celecoxib is a COX-2 inhibitor
  • Overexpression of COX-2 in cancer cells induces
    the production of VEGF, PDGF, bFGF and TGF-beta.
  • Through these angiogenesis mediators and their
    receptors on the endothelial cells, COX-2
    increased vascular permeability and induced
    endothelial cell proliferation and migration.
  • COX-2 overexpression led to the production of
    matrix metalloproteinase (MMPs), which have been
    implicated in extracellular matrix invasion
  • COX enzymes are essential for maintenance of the
    migration and attachment of endothelial cells
    through integrin pathways
  • Therefore a COX-2 inhibitor will block new vessel
    formation

16
Celecoxib
17
Endostatin
  • It was first discovered in 1995 in Dr. Folkmans
    lab
  • Phase I clinical studies began at M.D. Anderson
    November 1999
  • A naturally-occurring 20-kDa C-terminal fragment
    derived from type XVIII collagen.
  • Interfere with the pro-angiogenic action of
    growth factors such as basic fibroblast growth
    factor (bFGF/FGF-2) and vascular endothelial
    growth factor (VEGF)

18
Suramin
  • Developed by Oskar Dressel and Richard Kothe of
    Bayer, Germany in 1916
  • A polysulfonated naphthylurea
  • Is a prototype of a pharmacological antagonist of
    growth factors, including basic fibroblast growth
    factor (bFGF)
  • It is usually used for treatment of human
    sleeping sickness, onchocerciasis and other
    diseases caused by trypanosomes and worms

19
Thalidomide
  • One of the most perplexing drugs in medical
    history.
  • It is a hypnotic, causes peripheral nerve damage
    and severe birth defects, is anti-inflammatory,
    enhances the immune system, inhibits HIV
    replication, and inhibits some cancers
  • Thalidomide decreases TNF-a, tumor necrosis
    factor alpha levels,
  • TNF causes apoptotic cell death,
  • cellular proliferation,
  • differentiation,
  • inflammation, and
  • tumorigenesis

20
Thalidomide
21
Thalidomide
22
Summary
  • Angiogenesis inhibitors specifically halt new
    blood vessel growth and starve a tumor by cutting
    off its blood supply.
  • VEGF is responsible for the growth of new blood
    vessels. It promotes this growth by stimulating
    the endothelial cells, which form the walls of
    the vessels and transport nutrients and oxygen to
    the tissues.
  • Angiogenesis inhibitors prevent the VEGF from
    binding with the receptors on the surface of the
    endothelial cells.
  • There are 3 major types of anti-angiogenic
    therapies
  • Angiogenesis is the growth of blood vessels and
    is an important natural process used by the body
    for reproduction and for healing injured tissues

23
Citations
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  2. Wu, Z., et al., Biochem. Biophys. Res. Commun.,
    236, 651 (1997). 
  3. Boehm, T. Folkman, J. Browder, T. M. OReilly 
    Anti-angiogenic therapy of experimental cancer
    does not induce acquired drug resistance. Nature
    390, 404-407 (1997)
  4. Kim, K.J. Li, B. Winer, J. Armanini, M. Gillett,
    N. Phillips, H.S. N. Ferrara  Inhibition of
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    Nature 362, 841-844 (1993)
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    Webb, R. L.E. Smith Oligodeoxynucleotides
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    Chen, H. Riddle, L. Ferrara, N. King, G.L. L.E.
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