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

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

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Non-chemotherapeutic- refers to 'targeted therapy' drug ... Holds honorary degrees from fifteen universities and is the recipient of ... – PowerPoint PPT presentation

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


1
Avastin (Bevacizumab) Hallmark Anti-angiogenic
Non-chemotherapeutic Drug
  • Elizabeth Liao

2
Terminology
  • Bevacizumab- marketed as Avastin
  • Non-chemotherapeutic- refers to targeted
    therapy drug
  • Inhibits angiogenesis which is essential to tumor
    growth

3
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

4
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

5
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

6
Normal Body Blood Vessel Formation
  • Stages
  • A Vasculogenesis
  • B Angiogenic remodeling
  • C Stabilization and maturation
  • D Destabilization
  • E Regression
  • F Sprouting

7
Stage A Vasculogenesis
  • Undifferentiated
  • vascular bedding
  • during embryonic
  • development
  • Vascular
  • Endothelial Growth
  • Factor (VEGF) triggers this process

8
Stage B Angiogenesis
  • Pruning of primitive tubular network to form
    blood vessels
  • Vascular Endothelial Growth Factor (VEGF) is
    required

9
Stage C Stabilization and Maturation
  • Endothelial cells integrate
  • tightly with supporting cells
  • such as smooth muscle cells
  • and pericytes
  • Cell walls mature

10
Stage D Destabilization
  • Angiogenic sprouting into previously avascular
    tissue occurs
  • Distinct angiogenesis
  • from previous type
  • Only possible if pre-existing
  • vessels are first destabilized

11
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

12
Malignant Wilms Tumor
  • Most common type of kidney
  • tumor in children
  • Collagen IV stain

13
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

14
VEGF
  • 102 residues
  • 11 helical (2 helices 12 residues)
  • 57 beta sheet (8 strands 59 residues)

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

16
Figure 1 VEGF family ligands and receptors
Biochemical Society Transactions
www.biochemsoctrans.org Biochem. Soc.
Trans. (2003) 31, 1171-1177
17
(No Transcript)
18
Figure 2 VEGF signaling pathways
Biochemical Society Transactions
www.biochemsoctrans.org Biochem. Soc.
Trans. (2003) 31, 1171-1177
19
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

20
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)

21
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

22
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

23
Benefits
  • Non chemotherapeutic- biological agent that is
    less invasive to the body than chemotherapeutic
    agents
  • Half life of 20 days- good drug retention

24
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

25
Boxed WARNINGS and Additional Important Safety
Information
  • Gastrointestinal (GI) perforation
  • Wound healing complication
  • Hemorrhage
  • Neutropenia

26
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

27
Sorafenib
  • Orally available
  • Marketed by Bayer
  • Bis-aryl urea that is
  • a C-Raf kinase
  • inhibitor

28
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

29
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
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