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Anti-Angiogenesis Therapy for Cancer
Treatment: An Overview for Clinicians
Xiaodong Feng, PhD, PharmD
Associate Professor of Clinical Sciences
Department of Clinical and Administrative Sciences
California Northstate University College of Pharmacy
Disclaimer
The information within this presentation is for continuing
education purposes only, and is not intended to substitute for the
medical judgment of the healthcare provider. Recommendations
for use of any particular therapeutic agents or methods are based
upon the best available scientific evidence and clinical guidelines.
Reference in this activity to any specific commercial products,
process, service, manufacturer, or company does not constitute its
endorsement or recommendation.
Faculty Biography
International Journal of Cell Biology International Journal of Cell Biology. 2013; vol2013:1-11
International Journal of Cell Biology International Journal of Cell Biology. 2013; vol2013:1-11
Xiaodong Feng, PhD, PharmD
Associate Professor of Clinical Sciences
Department of Clinical and Administrative Sciences
California Northstate University College of Pharmacy
Rancho Cordova, CA95670
Developer’s Bio
EDUCATION:
B. S. Physiology, Nanjing University, Nanjing, China
Ph.D. Cellular & Molecular Physiology, Chinese Academy of Medical Sciences, Beijing, China
M.S. Computer Science , University of Bridgeport , Bridgeport, CT
PharmD, Albany College of Pharmacy, Albany, NY
LICENSES:
Registered Pharmacist, California State Board of Pharmacy
Registered Pharmacist, New York State Board of Pharmacy
Topic Related Publication:
 International Journal of Cell Biology. 2013; vol2013:1-11
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Int Angiol. 2006 Dec;25(4):407-13.
J Cardiovasc Pharmacol. 2006 Aug;48(2):6-13.
J. Invest. Derm. 5; 40-46, 2000.
Faculty Disclosures
●
Dr. Feng has nothing to disclose. He does not intend to
discuss non-FDA approved drugs or investigational use of
any products.
Objectives
•
•
•
•
•
•
1) Understand the physiology and pathophysiology of
angiogenesis
2) Recognize angiogenesis as an essential hallmark feature of
solid tumor development
3) Identify the potential drug targets for anti-angiogenesis
therapy
4) Discuss and differentiate the mechanisms of action for the
FDA approved anti-angiogenesis cancer drugs
5) Evaluate the triumphs and limitations of anti-angiogenesis
cancer treatments
6) Assess the treatment strategies and follow up plans of antiangiogenesis cancer treatment
Physiology of Angiogenesis
• Definition: Angiogenesis is the growth of new blood
vessels from pre-existing vessels
red blood cell
endothelial cell capillary lumen
this endothelial cell will
generate a new capillary
branch
pseudopodial process guides the
development of the capillary
sprout as it grows into the
surrounding connective tissue
capillary sprout
hollows out to
form tube
(The Cell 4th ed 2002)
Physiology of Angiogenesis
• Angiogenesis is a dynamic and complicated multistep
process involving vascular endothelial:
 Activation
 Invasion
 Migration
 Proliferation
 Sprout formation
 Tube formation
 Capillary network formation
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
In Vitro Sprouting Angiogenesis of Human Dermal
Microvascular Endothelial Cells
Presence of Multiple Cells and Lumen
International Journal of Cell Biology. 2013; vol2013:1-11
Sprouting Angiogenesis in Wound Healing
dermis
clot
J. Invest. Derm. 5; 40-46, 2000.
Angiogenesis: Physiology and Pathophysiology
• Angiogenesis is an important process in physiological
conditions:
 Wound healing
 Reproduction
 Embryonic development
• Angiogenesis also plays an essential role in the
pathophysiological conditions:
 Solid tumor growth
Psoriasis
Diabetic retinopathy
 Macular Degeneration
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Angiogenesis: Physiology and Pathophysiology
• Under normal physiologic conditions, angiogenesis is well
controlled by the local balance between endogenous
angiogenesis stimulators and angiogenesis inhibitors,
although the regulatory mechanism is still not clear.
• During wound healing, the expression of vascular
endothelial growth factor (VEGF), one of the most potent
angiogenic stimulators is significantly upregulated to
promote wound healing by restoring blood flow to injured
tissues.
Cancer Res 2005;65:3967-3979
Dynamic regulation of angiogenesis in wound healing: more
angiogenesis in fibrin rich wound clot, less in collagen rich scar
International Journal of Cell Biology. 2013; vol2013:1-11
Angiogenesis: Physiology and Pathophysiology
• Deficient production of angiogenic stimulators turns
off angiogenesis switch and leads to insufficient
angiogenesis.
• Inordinate production of angiogenic stimulators
turn on the angiogenesis switch and drives
excessive angiogenesis.
• Both insufficient and excessive angiogenesis
contribute to the pathogenesis of many major
diseases
• Thus discovering endogenous and exogenous
angiogenic inhibitors provides potential drug targets
to block angiogenesis for solid tumors.
Cancer Res 2005;65:3967-3979.
Examples of Angiogenesis Stimulators
Vascular endothelial growth factor (VEGF)
Fibroblast growth factor (bFGF/aFGF)
Placental growth factor (PlGF)
Platelet-derived growth factor (PDGF)
Transforming growth factor (TGF)
Developmental endothelial locus-1 (Del-1)
Tumor necrosis factor alfa (TNF-α)
Interleukin-8 (IL-8)
Hepatocyte growth factor (HGF)
Platelet derived endothelial cell growth factor (PD-ECGF)
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Examples of Angiogenesis Inhibitors
Matrix derived
Arresten
Canstatin
Endorepellin
Endostatin
Fibronectin fragment
(Anastellin)
ECM-binding integrins
Fibulin
Thrombospondin-1 and -2
Tumstatin
Non-matrix derived
Cytokines
Interferons
Interleukins
Pigment epithelium derived factor
(PEDF)
Fragments of blood coagulation
factors
Angiostatin
Antithrombin III
Prothrombin kringle 2
Platelet factor-4
Pharmaceuticals 2010, 3, 3021-3039;
Angiogenesis and Solid Tumor Development
. J Natl Cancer Inst. 2006;98:316-325.
Sustained Angiogenesis is a hallmark feature of solid tumors!
Cell. 2011;144:646-674
•Hypoxia occurs in
overgrowing tumors
•Hypoxia causes
accumulation of HIF
(hypoxia induced
factor)
•HIF transports into
the nucleus and
induces the expression
VEGF and other target
genes.
•VEGF is one of the
main angiogenic
stimualtors
Angiogenesis and Solid Tumor
• Progressive solid tumor growth is dependent on angiogenesis
•
Most tumors in human persist in situ for a long period of time
in an avascular and quiescent status
• The tumor switches to an angiogenic phenotype by a change
in the balance between positive and negative regulators of
angiogenesis , to invoke new capillary network formation
• New Blood vessels provide nutrients for tumor growth
• The expending tumor mass invade blood vessels and
neoplastic cells disseminate in the blood stream inducing
metastasis.
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9
Anti-Angiogenesis Therapy for Cancer
• The investigation to inhibit tumor angiogenesis has
shed new light on cancer treatment.
• The FDA approved almost twenty molecularly
targeted anti-angiogeneis therapeutic drugs for
cancer treatment,
• Anti-angiogenesis therapy represents one of the most
significant advances in clinical oncology.
• More research needs to fully understand the
biological mechanisms of tumor angiogenesis to
optimize this new cancer treatment strategy
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Strategies for Anti-Antiangiogenesis Therapy
• Restore the dynamic balance between angiogenic
inhibitors and angiogenic stimulators
---Decrease the production or activities of angiogenic
stimulators, such as VEGF
---Increase the production and activities of angiogenic
inhibitors, such as endostatin
• Disrupt the major components of angiogenesis process
---Inhibiting the activation of vascular endothelial cells
---Blocking endothelial adhesion , migration, invasion
and tube formation
Potential Molecular Targets for Anti-angiogenesis
• Many enzymes, growth factors, extracellular matrix
(ECM) proteins, ECM receptors and their signal
transduction pathways .
• Drugs based on blocking monoclonal antibodies and
chemical inhibitors are being developed to block the
effect of angiogenesis growth factors.
• Since VEGF plays an essential role in stimulating
tumor angiogenesis, blocking VEGF mediated
signaling pathways has been one of the major
strategy for anti-angiogenesis therapy.
VEGF: The Main Molecular Target for Anti-angiogenesis
• Currently, there are six members in the family of
VEGFs, i.e. VEGF-A, -B, -C, -D, -E, and placenta growth
factor (PlGF).
• The VEGF family proteins bind in a distinct pattern to
three structurally related receptor tyrosine kinases
known as VEGF receptor (VEGFR)-1, -2, and -3.
• Blocking antibodies, synthetic or natural proteins
against VEGF or VEGFR, and inhibitors of VEGF
receptor tyrosine kinase and its downstream signal
transduction pathway are some of the major antiangiogenesis therapeutic agents.
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Anti-angiogenesis Drug Targets:
Monoclonal antibody to VEGF
Ribozyme targeting VEGF mRNA
VEGF antisense oligonucleotide
VEGF receptor inhibitor
Soluble decoy receptor to trap VEGF
VEGFR-2 inhibitor peptide
VEGFR/PDGFR dual kinase inhibitor
VEGFR1 peptide vaccine
VEGFR2 peptide Vaccine
Small molecule VEGF RTK inhibitor
mTOR inhibitors
Bevacizumab (Avastin)
Angiozyme
GEM 220, Veglin
PTK787/ZK222584
VEGF Trap (Afilbercept)
CT-322
TAK-593
VEGFR1-1084 peptide vaccine
VEGFR2-169 peptide vaccine
sunitinib (Sutent)
sorafenib (Nexavar)
temsirolimus (CCI-779)
everolimus (RAD001),
FDA Approved Anti-angiogenesis Therapy:
bevacizumab (Avastin)
Mechanism of Action
• Bavacizumab is the first anti-angiogenesis therapy agents
approved by the FDA.
• It is recombinant humanized monoclonal antibody directed
against VEGF-A which is widely expressed in many solid human
cancers.
• It inhibits formation of new blood vessels in primary tumor and
metastatic tumors.
FDA Approved Anti-angiogenesis Therapy:
bevacizumab (Avastin)
Approved Indication
• First-line therapy to treat metastatic colorectal cancer in
combination with 5-fluorouracil. It is not indicated for adjuvant
treatment of colon cancer
• Second-line therapy to treat metastatic colorectal in
combination with FOLFOX-4.
• To treat non-squamous non–small cell lung cancer in
combination with carboplatin/paclitaxel.
• Approved as a single agent treatment for glioblastoma with
progressive disease following prior therapy.
• To treat renal cell cancer in combination with interferon-alpha
Efficacy of Bevacizumab:
Metastatic Colorectal Cancer (mCRC)
IFL + Avastin
5 mg/kg q 2 wks
* p < 0.001 by stratified log rank test. † p < 0.01 by χ2 test.
Number of Patients
411
402
Overall Survival*
Median (months)
15.6
20.3
Hazard ratio
0.66
Progression-free Survival*
Median (months)
6.2
10.6
Hazard ratio
0.54
Overall Response Rate†
Rate (percent)
35%
45%
Duration of Response
Median (months)
7.1
IFL + Placebo
IFL (irinotecan 125 mg/m2, 5-FU 500 mg/m2, and leucovorin (LV) 20 mg/m2 given once
weekly for 4 weeks every 6 weeks)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=93
9b5d1f-9fb2-4499-80ef-0607aa6b114e
FDA Approved Anti-angiogenesis Therapy:
bevacizumab (Avastin)
Black Box Warning
• Gastrointestinal Perforation: Occurs in up to 2.4% of Avastintreated patients. Discontinue Avastin for gastrointestinal
perforation.
• Surgery and Wound Healing Complications: Discontinue in
patients with wound dehiscence. Discontinue at least 28 days
prior to elective surgery. Do not initiate Avastin for at least 28
days after surgery and until the surgical wound is fully healed.
• Hemorrhage: Severe or fatal hemorrhage, hemoptysis,
gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding
are increased in Avastin- treated patients. Do not administer
Avastin to patients with serious hemorrhage or recent
hemoptysis.
Clinical Considerations for Bevacizumab (1)
• Do not infuse in a dextrose containing solution.
• Increased risk of arterial thromboembolic events, including
myocardial infarction and stroke. Risk factors are age >65 years
and history of angina, stroke, and prior arterial
thromboembolic events.
• Potential for serious and, in some cases, fatal hemorrhage
resulting from hemoptysis in patients with non squamous
non–small cell lung cancer.
• Patients with recent hemoptysis (>1/2 tsp of red blood)
should not receive bevacizumab.
Clinical Considerations for Bevacizumab (2)
• Use with caution in patients who have undergone recent
surgical and/or invasive procedures.
• Bevacizumab should be given at least 28 days after any
surgical and/or invasive intervention.
• In patients who have undergone surgical resection of the liver,
bevacizumab should not be given for at least 6 to 8 weeks
after the surgical procedure.
• Use with caution in patients with uncontrolled hypertension .
Discontinued in patients with hypertensive crisis.
Clinical Considerations for Bevacizumab (3)
• Discontinue in patients with nephrotic syndrome. Hold for
proteinuria >2 grams/24 hours and resumed when <2 grams/24
hours.
• Reversible posterior leukoencephalopathy syndrome (RPLS) can
occur from 16 hours to 1 year after initiation of bevacizumab
• Infusion-related symptoms with fever, chills, urticaria, flushing,
fatigue, headache, bronchospasm, dyspnea, angioedema, and
hypotension can be treated by benadryl and acetaminophen.
• Although bevacizumab is pregnancy category B, don’t recommend
it for pregnancy, since angiogenesis is essential for embryonic
development.
Anti-angiogenesis Therapy: ziv-aflibercept (Zaltrap)
Mechanism of Action
• Ziv-Aflibercept is a fused protein comprised of segments of the
extracellular domains of human VEGF receptors 1 (VEGFR1) and
2 (VEGFR2), and constant region (Fc) of human IgG.
• Afilbercept inhibits angiogenesis by functioning as a soluble
decoy receptor to trap VEGFs.
Indication:
• It is indicated in combination with FOLFIRI (5-fluorouracil,
leucovorin, irinotecan) for patients with metastatic colorectal
cancer (mCRC) that is resistant to or has progressed following an
oxaliplatin-containing regimen.
• Warning and toxicity: very similar to bevacizumab
Efficacy of Zaltrap in mCRC resistant to oxaliplatin-based
combination chemotherapy, with or without prior bevacizumab
Placebo/FOLFIRI
(N=614)
Overall Survival
Number of deaths, n (%)
ZALTRAP/FOLFIRI
(N=612)
Stratified Hazard ratio (95% CI)
460 (74.9%)
403 (65.8%)
12.06 (11.07 to
13.50 (12.52 to
13.08)
14.95)
0.817 (0.714 to 0.935)
Stratified Log-Rank test p-value
0.0032
Median overall survival (95% CI) (months)
Progression Free Survival (PFS)
Number of events, n (%)
Median PFS (95% CI) (months)
Stratified Hazard ratio (95% CI)
Stratified Log-Rank test p-value
Overall Response Rate (CR+PR) (95% CI)
(%)
Stratified Cochran-Mantel-Haenszel test
p-value
454 (73.9%)
4.67 (4.21 to 5.36)
393 (64.2%)
6.90 (6.51 to 7.20)
0.758 (0.661 to 0.869)
0.00007
11.1 (8.5 to 13.8)
19.8 (16.4 to 23.2)
0.0001
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d
Anti-angiogenesis Therapy:
Angiogenic Signal Inhibition
• The discovery of downstream signal-transduction
pathways for RTK has also led to the development of
many new targeted agents.
• The three major signal transduction pathways for
angiogenic growth factors RTK include the
Ras/Raf/MAPK pathway, PI3K/Akt/ mTOR pathway and
PKC pathway.
US Pharmacist. 2010;35(7) (Oncology Suppl):4-9.
Anti-angiogenesis Drug Targets :
RTK Small Molecule Inhibitors
• In addition to the ligand blocking agents, anti-angiogenesis
drugs are also being developed to block the signal
transduction pathway for angiogensis stimulators.
• Several small molecular weight receptor tyrosine kinase
(RTK) inhibitors, such as sunitinib and sorafenib, have been
developed to target the signal transduction pathway of
angiogenic stimulators:
–
–
–
–
–
–
platelet-derived growth factor receptors (PDGFRα and PDGFRβ),
vascular endothelial growth factor receptors (VEGFR1, 2, 3)
Stem cell factor receptor (KIT),
Fms-like tyrosine kinase-3 (FLT3),
Colony stimulating factor receptor Type 1 (CSF-1R),
Glial cell-line derived neurotrophic factor receptor RET)
Anti-angiogenesis Drug Targets : RTK Small Molecule Inhibitors
RTK Inhibitors
Main Targets
Indications
Sunitinib
(Sutent)
PDGFR , VEGFR1, 2, 3
KIT, FLT3, CSF-1R, RET
gastrointestinal stromal tumor after disease
progression on or intolerance to imatinib
Sorafenib
(Nexavar)
RAF, KIT, FLT-3, VEGFR-1, 2,
3, RET, and PDGFR
Unresectable hepatocellular carcinoma
Advanced renal cell carcinoma
Vandetanib
(Caprelsa)
EGFR, VEGFR , RET, BRK,
TIE2, EPH receptor and Src
treatment of symptomatic or progressive
advanced medullary thyroid cancer
Cabozantinib
(Cometriq)
RET, MET, VEGFR-1, 2, 3, KIT, progressive, metastatic medullary thyroid cancer
TRKB, FLT-3, AXL, and TIE-2 (MTC)
Axitinib
(Inlyta)
VEGFR)-1, 2, 3
advanced renal cell carcinoma after failure of
one prior systemic therapy
Regorafenib
(Stivarga)
RET, VEGFR1, 2, 3, KIT,
PDGFR, FGFR, TIE2, DDR2,
TrkA, Eph2A, RAF-1, and Abl
Metastatic colorectal cancer (CRC)
Locally advanced, unresectable or metastatic
gastrointestinal stromal tumor (GIST)
Pazopanib
(Votrient)
VEGFR-1, 2, 3, PDGFR, FGFR, advanced renal cell carcinoma
Kit, Itk, Lck), and c-Fms
advanced soft tissue sarcoma
Anti-angiogenesis Drug Targets : RTK Small Molecule Inhibitors
RTK Inhibitors
Black Box Warning
Sunitinib
(Sutent)
Hepatotoxicity may be severe, and deaths have been reported
Sorafenib
(Nexavar)
N/A
Vandetanib
(Caprelsa)
QT interval prolongation, Torsades de pointes , Do not use in patients with
long QT syndrome, correct hypocalcemia, hypokalemia, hypomagnesemia
Cabozantinib
(Cometriq)
Perforations and Fistulas; Severe, sometimes fatal, hemorrhage including
hemoptysis and gastrointestinal hemorrhage
Axitinib
(Inlyta)
N/A
Regorafenib
(Stivarga)
Severe and sometimes fatal hepatotoxicity. Monitor hepatic function prior to
and during treatment.
Pazopanib
(Votrient)
Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor
hepatic function and interrupt, reduce, or discontinue dosing as recommended
Anti-angiogenesis Drug Targets :
mTOR Inhibitors
• Mammalian target of rapamycin (mTOR) is one of the key
protein kinases controlling signal transduction from various
angiogenic stimulators and upstream proteins to the level of
mRNA translation and ribosome biogenesis.
• mTOR plays vey critical role in regulating cell cycle
progression, cellular proliferation and growth, and
angiogenesis.
• In 2007, the FDA approved temsirolimus (Torisel), the first
drug in the class of mTOR inhibitors, for metastatic renal cell
carcinoma (RCC).
• In 2009, the FDA approved everolimus (Afinitor), a second
drug in the class of mTOR inhibitors, for the treatment of
advanced RCC after failure of treatment with sunitinib or
sorafenib.
Clinical Considerations of mTOR Inhibitors (1)
• Use with caution in patients with hepatic impairment, and
dose reduction and/or interruption should be considered.
• Premedicated with an diphenhydramine to reduce the
incidence of hypersensitivity reactions.
• Closely monitor triglycerides, cholesterol, serum glucose
levels in all patients, especially those with diabetes mellitus.
• Closely monitor patients for new or progressive pulmonary
symptoms, including cough, dyspnea, and fever, hold
Temsirolimus for pulmonary toxicity
• It is a strong immunosuppressant, patients are at increased
risk for developing opportunistic infections
Clinical Considerations of mTOR Inhibitors (2)
• It is a strong immunosuppressant, patients are at increased
risk for developing opportunistic infections, avoid live vaccine
• Adjust dose with CYP3A4 inhibitor, such as ketoconazole,
itraconazole, erythromycin, clarithromycin, and grapefruit
• Adjust dose with CYP3A4 inducers, such as phenytoin,
carbamazepine, rifampin, phenobarbital, and St. John’s Wort
• Avoid alcohol or mouthwashes containing peroxide in the
setting of
• oral ulcerations as they may worsen the condition.
• Prengancy category D
Other Anti-angiogenesis Drugs:
thalidomide (Thalomid)
Mechanism of Action
• May exert an anti-angiogenic effect through inhibition of basic
FGF and VEGF as well as through as yet undefined
mechanisms.
Indication
• To treat newly diagnosed multiple myeloma in combination
with dexamethasone
• To treat cutaneous manifestations of erythema nodosum
leprosum (ENL).
Other Anti-angiogenesis Drugs:
thalidomide (Thalomid)
Black Box Warning
• Embryo fetal toxicity, pregnancy category X
• It is only available through a restricted distribution program, the
THALOMID REMS™ program (formerly known as (S.T.E.P.S.)
program)
• Significant increased risk of deep vein thrombosis (DVT) and
pulmonary embolism (PE)
Other Clinical Considerations
• Men taking thalidomide must use latex condoms for every sexual
encounter with a woman of childbearing potential
• HIV mRNA levels may be increased while on thalidomide.
• It can cause drowsiness, avoid operating heavy
machinery or driving a car while on thalidomide
• Risk of serious skin reactions, Stevens-Johnson syndrome
Other Anti-angiogenesis Drugs:
lenalidomide (Revlimid)
Mechanism of Action
• May exert an anti-angiogenic effect through
inhibition of basic FGF and VEGF as well as
through as yet undefined mechanisms.
Indication
• Myelodysplastic syndrome: 10 mg PO daily.
• To treat multiple myeloma in combination with
dexamethasone
Other Anti-angiogenesis Drugs:
lenalidomide (Revlimid)
Black Box Warning
• Embryo fetal toxicity, pregnancy category X
• REVLIMID REMS™ distribution program (formerly known as the
“RevAssist® program”
• Significant neutropenia and thrombocytopenia
• Significant risk of DVT) and PE
Other Clinical Considerations
• Men on this drug must use latex condoms for every sexual
encounter with a woman of childbearing potential,
• Should not donate blood or semen while receiving treatment,
and for at least 1 month after
• Toxic to the bone marrow. Adjust dose for liver dysfunction
Prospective Anti-angiogenesis Therapy Target (1):
PTK787/ZK222584
• The VEGF receptor inhibitor PTK787/ZK222584 in
combination with standard chemotherapy is in phase
III clinical trials for colorectal cancer.
• It is also in phase II clinical trials for a number of other
tumors, such as metastatic gastrointestinal stromal
tumors, unresectable malignant mesothelioma.
Prospective Anti-angiogenesis Drug Targets (2):
Regulating Tumor Microenvironment
• The 3D extracellular matrix environment also plays an
active role in the regulation of angiogenesis by dynamic
interaction between vascular endothelial cells and
extracellular matrix.
• A study by Cheresh and his colleagues indicated that
integrin alpha v beta 3, the receptor for fibrinogen,
vitronectin, fibronectin and other matrix proteins, is the
marker of sprout angiogenesis.
• Blocking antibodies and chemical inhibitors of integrin
alphaV beta3 significantly inhibit tumor angiogenesis.
Prospective Anti-angiogenesis Drug Targets (3):
Regulating Tumor Microenvironment
• Many endogenous inhibitors of angiogenesis are fragments
of larger extracellular matrix (ECM) molecules.
• These fragments become released upon proteolysis of the
ECM and the vascular basement membrane by enzymes,
such as matrix metalloproteinases (MMPs), cathepsins and
elastases.
• Dr. Folkman’s laboratory discovered that endostatin, a
naturally-occurring 20-kDa C-terminal fragment derived
from type XVIII collagen, significantly inhibits tumor growth
by blocking tumor angiogenesis.
Anti-angiogenesis Drug Targets (4):
Regulating Tumor Microenvironment
• Regulation of hypoxia induced Factor 1α (HIF-1α) and
extracellular marix (ECM) breakdown plays important
role in angiogenesis.
• Vascular disrupting agents, including tubulin
destabilizers that also inhibit HIF-1α expression, may
be used to disrupt tumor blood vasculature.
Examples of Prospective Anti-angiogenesis Drug Targets
Blocking ECM
degradation
Matrix
metalloproteinase
(MMP) inhibitors
Urokinase/plasmin
inhibitors
Endogenous
Plasminogen and
angiogenesis inhibitor collagen
XVIII,degradation
fragments
Vascular targeting
Aminopeptidase N,
agents
tubulin
Hypoxia cell
Hypoxia agents
BMS275291,COL3,Neovastat
WX-UK, WK293
Angiostatin,
Endostatin, 2ME
2
ZD6126,
CA4P,NGR
peptides
Tirapazamine,
Anti-angiogenesis Drug Targets (5):
Other targets
• Histone deacetylase (HDAC) inhibitors modulate the
expression of angiogenesis-related genes, such as
hypoxia-inducible factor-1alpha (HIF-1a) and vascular
endothelial growth factor (VEGF), NF-κB modulation.
• Copper also play important role in the regulation of
tumor angiogenesis
Anti-angiogenesis Drug Targets: Other targets
Epigenetic modification
Histone deacetylase
(HDAC)
DNA methyltransferase
(DNMT) inhibitors
LBH589,
NFkB
Proteasome inhibitors
PS-341
Copper
Copper chelator
Ammonium
tetrathiomolybdate
5-aza-2'deoxycytidine,
zebularine
Anti-angiogenesis Drug Targets (3):
Other targets
• There are at least 30 known endogenous angiogenesis
inhibitors found in the body, they are also potential
drug targets for anti-angiogenesis therapy.
• Angiogenesis inhibitors have also been discovered from
natural sources, including: tree bark, fungi, shark
muscle and cartilage, sea coral, green tea, and herbs
(licorice, ginseng, cumin, garlic).
• In total, more than 300 angiogenesis inhibitors have
been discovered to date.
Anti-angiogenesis Drug Targets (3):
Other targets
• There are at least 30 known endogenous angiogenesis
inhibitors found in the body, they are also potential
drug targets for anti-angiogenesis therapy.
• Angiogenesis inhibitors have also been discovered from
natural sources, including: tree bark, fungi, shark
muscle and cartilage, sea coral, green tea, and herbs
(licorice, ginseng, cumin, garlic).
• In total, more than 300 angiogenesis inhibitors have
been discovered to date.
SUMMARY
• Anti-angiogenesis therapy represents one of the most
significant advances in clinical oncology.
• More research needs to fully understand the biological
mechanisms of tumor angiogenesis to optimize this new
cancer treatment strategy.
• More drugs are still in development to increase the target
specificity and to investigate their roles in the treatment of
different cancers.
• Although majority of the approved anti-angiogenesis drugs
only offers a modest survival benefit in a limited patient
population, they paves the way for the development of
more optimized anti-angiogeneis strategy for cancer
treatment.
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Xiaodong Feng
Associate Professor
College of Pharmacy
California Northstate University
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