Anti-Angiogenic Cancer Therapies

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Anti-Angiogenic Cancer Therapies

• Tangela S. Feemster
• Tuesday, March 27, 2007
• Dr. Buynak
• Medicinal Chemistry

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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.

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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).

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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
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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.

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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.

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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
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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

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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.

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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.

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Specific Angiogenic Inhibitors

• Angiostatin
• Avastin (Bevacizumab)
• Celebrex (Celecoxib)
• Endostatin
• Metaret (Suramin)
• Thalidomide

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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.

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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.

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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

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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

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Celecoxib
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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)

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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

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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

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Thalidomide
21
Thalidomide
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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

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