Avastin (Bevacizumab) : Hallmark Anti-angiogenic Non-chemotherapeutic Drug

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Avastin (Bevacizumab) Hallmark Anti-angiogenic
Non-chemotherapeutic Drug

• Elizabeth Liao

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Terminology

• Bevacizumab- marketed as Avastin
• Non-chemotherapeutic- refers to targeted
  therapy drug
• Inhibits angiogenesis which is essential to tumor
  growth

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Judah Folkman Father of Angiogenesis

• First person to observe
• angiogenesis as
• having pathological
• Implications in cancer in 1971
• Born in Cleveland in 1933
• Began his surgical residency
• at the Massachusetts General
• Hospital and served as chief
• resident in surgery from 1964-1965

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Folkman Facts

• While serving as a lieutenant in the U.S. Navy
  from 1960-1962, Folkman and a colleague first
  reported the use of silicone rubber implantable
  polymers for the sustained release of drugs
• Formed basis of development of Norplant

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Accomplishments

• Author of 389 original peer-reviewed papers and
  106 book chapters and monographs
• Holds honorary degrees from fifteen universities
  and is the recipient of numerous national and
  international awards
• Elected to the National Academy of Sciences, the
  American Academy of Arts and Sciences, the
  American Philosophical Society and the Institute
  of Medicine of the National Academy
• of Sciences

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Normal Body Blood Vessel Formation

• Stages
• A Vasculogenesis
• B Angiogenic remodeling
• C Stabilization and maturation
• D Destabilization
• E Regression
• F Sprouting

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Stage A Vasculogenesis

• Undifferentiated
• vascular bedding
• during embryonic
• development
• Vascular
• Endothelial Growth
• Factor (VEGF) triggers this process

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Stage B Angiogenesis

• Pruning of primitive tubular network to form
  blood vessels
• Vascular Endothelial Growth Factor (VEGF) is
  required

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Stage C Stabilization and Maturation

• Endothelial cells integrate
• tightly with supporting cells
• such as smooth muscle cells
• and pericytes
• Cell walls mature

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Stage D Destabilization

• Angiogenic sprouting into previously avascular
  tissue occurs
• Distinct angiogenesis
• from previous type
• Only possible if pre-existing
• vessels are first destabilized

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Tumor Angiogenic Dependency

• Tumor- undesired growth of cells
• Once a tumor grows beyond 100-200 µM in size, the
  development of new vasculature becomes essential
  to maintain adequate tumor oxygenation and
  sustained tumor growth

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Malignant Wilms Tumor

• Most common type of kidney
• tumor in children
• Collagen IV stain

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Vascular Endothelial Growth Factor

• Glycoproteins consisting of A-, B-, C-, D-, E-
  forms and Placenta Growth Factor (PLGF)
• Within the six subtypes multiple isoforms exist
• Loss of even a single VEGF-A allele results in
  embryonic lethality due to cardiac complications

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VEGF

• 102 residues
• 11 helical (2 helices 12 residues)
• 57 beta sheet (8 strands 59 residues)

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VEGF Receptors

• 3 types of receptors- VEGFR-1, VEGFR-2 (KDR,
  Flk-1), VEGFR-3
• Tyrosine kinases
• 316 residues
• 35 helical
• 15 beta sheet

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Figure 1 VEGF family ligands and receptors
Biochemical Society Transactions
www.biochemsoctrans.org Biochem. Soc.
Trans. (2003) 31, 1171-1177
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(No Transcript)
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Figure 2 VEGF signaling pathways
Biochemical Society Transactions
www.biochemsoctrans.org Biochem. Soc.
Trans. (2003) 31, 1171-1177
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Avastin Bevacizumab- Reach Beyond Convention

• Recombinant, humanized monoclonal antibody that
  binds to all isoforms of VEGF-A such that KDR
  signaling is inhibited
• Developed by Genentech BioOncology
• Not a chemotherapy drug Targeted Therapy

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Bevacizumab Continued

• FDA-approved for first and second-line treatment
  of colorectal and rectum cancer in combination
  with oxaliplatin, leucovorin and fluorouracil
  (FOLFOX4) in 2004
• Approved for first-line treatment of Non-Small
  Cell Lung Cancer in combination with Carboplatin
  and Paclitaxel
• Previously investigated in combination with
  Fluorouracil in phase II and III trials in a wide
  variety of tumors
• Study results initially presented at the 2003
  Annual Meeting of the American Society of
  Clinical Oncology (ASCO)

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Efficacy

• Adding Bevacizumab to chemotherapy results in
  increased median Progression Free Survival by 33
• Median survival was 15.1 and 18.3 months in the
  Leucovorin (IFL)/placebo, and 5-FU/LV/Bevacizumab
  trial groups respectively
• Overall Response Rate and duration of response
  were also increased in the Bevacizumab-containing
  group

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Dosage

• Colorectal and rectum cancer
• AVASTIN in combination with intravenous
  5-FU-based chemotherapy
• - 5 mg/kg or 10 mg/kg every 14 days
• AVASTIN in combination with bolus-IFL
• - 5 mg/kg
• AVASTIN in combination with FOLFOX4
• - 10 mg/kg
• Non-Squamous, Non-Small Cell Lung Cancer
• 15 mg/kg, as an IV infusion every 3 weeks

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Benefits

• Non chemotherapeutic- biological agent that is
  less invasive to the body than chemotherapeutic
  agents
• Half life of 20 days- good drug retention

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Concerns

• Since Bevacizumab is expected to inhibit new
  angiogenic growth, concerns have been raised
  regarding postoperative wound-healing and
  bleeding complications in patients who undergo
  surgery within 1 to 2 months of Bevacizumab
  therapy

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Boxed WARNINGS and Additional Important Safety
Information

• Gastrointestinal (GI) perforation
• Wound healing complication
• Hemorrhage
• Neutropenia

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Future Directions-VEGF-Trap

• Composite decoy receptor based on VEGFR-1 and
  VEGFR-2 fused to a human Fc segment of IgG1 that
  binds VEGF
• Decreases free VEGF to bind to receptors and
  prevent vessel growth
• FDA approved for macular degeneration

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Sorafenib

• Orally available
• Marketed by Bayer
• Bis-aryl urea that is
• a C-Raf kinase
• inhibitor

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Conclusions

• Single effective combination drug treatment for
  all types of tumors is still far from being
  developed
• Multiple types of combination therapy in
  conjunction with each other are essential to
  successful treatment of tumors

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References

• 1. Peter Carmeliet, Rakesh K. Angiogenesis in
  cancer and other diseases. Nature 407, 249-257
  (14 September 2000)
• 2. Napoleone Ferrara, Robert S. Kerbel.
  Angiogenesis as a therapeutic target. Nature 438,
  967-974 (15 December 2005)
• 3. Alberto Sobrero, Paolo Bruzzi. Bevacizumab
  Plus Fluorouracil The Value of Being Part of a
  Developing Story. Journal of Clinical Oncology,
  Vol 23, No 16 (June 1), 2005 pp. 3660-3662.
• 4. George D. Yancopoulos, et al.
  Vascular-specific growth factors and blood vessel
  formation. Nature 407, 242-248 (14 September
  2000)
• 5. Herbert I. Hurwitz, et al. Bevacizumab in
  Combination With Fluorouracil and Leucovorin An
  Active Regimen for First-Line Metastatic
  Colorectal Cancer. Journal of Clinical Oncology,
  Vol 23, No 15 (May 20), 2005 pp. 3502-3508
• 6. Avastin.com
• 7.http//cancerpublications.com/newsletter/other/V
  EGF/v1n1/kabbinavar/index.html