clinical significance of angiogenesis inhibitors in the treatment
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Clinical significance of angiogenesis Clinical significance of angiogenesis inhibitors in the treatment of cancerinhibitors in the treatment of cancer
Łukasz ŁapińskiAnna Wiela-Hojeńska
Krystyna Orzechowska-Juzwenko
Department of Clinical Pharmacology
Wrocław Medical University
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AngiogenesisAngiogenesis
(gr. angeion- blood vessel, genesis- formation)
a process of new blood vessels formation
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Angiogenesis plays important role in many physiological conditions,
e.g. fetal development, female reproductive cycle or
wound healing
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The angiogenic process is regulated by balance between
endogenous proangiogenicand angiogenic factors
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Stimulatory and inhibitory factors of angiogenesis
Lim S.T., Levine A.M.: Angiogenesis and hematological malignancies. Hematology, 2005, 10, 11-24.
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Others stimulators and inhibitors of angiogenesis1. Stimulators:• angiogenin• cyclooxygenase-2• erythropoietin• β- estradiol• G-CSF• interleukin (IL) 8• matrix metalloproteases (MMP)• nitric oxide• tumor necrosis factor α• vascular endothelial growth
factor (VEGF)
2. Inhibitors:• heparinases• heparin hexasaccharide
fragment• interferon- α, β, γ• IL 4, IL 12, IL 18• 2- methoxyestradiol• plasminogen activator
inibitors• prolactin 16kDa fragment• retinoids• tetrahydrocortisol-S
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Role Role inin thethe formationformation ofofnewnew vesselsvessels
Erythropietin Nitric oxide
• ↑ endothelial cellsproliferation
• ↑ angiogenesis in vivo
• ↑ permeability
• ↑ endothelial cellsproliferation
• ↑ fibroblast growth factorliberation
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Angiogenesis also plays Angiogenesis also plays important role in pathogenesis important role in pathogenesis
of many diseasesof many diseases
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In pathological conditions balance between angiogenesis stimulators and inhibitors is
disturbed
Nyberg P., Xie L., Kalluri R.: Endogenous inhibitors of angiogenesis. Cancer Res., 2005, 65, 3967-3979
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Role of angiogenesis in diseasesRole of angiogenesis in diseases
Angiogenesis
1. Cancer
2. Rheumatoid arthritis
3. Ophtalmia
4. Psoriasis
5. AIDS complications
Angiogenesis
1. Ictus
2. Infertility
3. Scleroderma
4. Ulcer
5. Cardiomyopathy
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Growth of cancer depends on an adequate supply of oxygen, nutrients and the removal of
waste products
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Angiogenic process may be initiated by
• hypoxia in cancerous cells
• mutation in suppressor genes
• mutation in oncogenes
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The process of angiogenesis
Pandya N.M., Dhalla N.S., Santani D.D.: Angiogenesis- a new target for futuretherapy. Vascular Pharmacol., 2006, 44, 265-274.
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Angiogenesis also plays an important role in spread of
solid tumors
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Role of angiogenesis in cancer development, its growth and formation of metastasis
Hoeben A., Landuyt B., Highley M.S., Wildiers H., van Oosterom A.T., de Bruijn E.A.: Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev., 2004, 56, 549-580.
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AAngiogenesisngiogenesis inhibitorsinhibitors
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Inhibition levels of tumoral angiogenesis
Shinkaruk S., Bayle M., Lain G., Deleris G.: Vascular endothelial cell growthfactor , an emerging target for cancer chemotherapy. Curr. Med. Chem.- Anti-cancer agents, 2003, 3, 95-117.
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Angiogenesis can be stopped or altered by:
• blocking initial signals from the tumor• making initial signals from the tumor
less effective• stopping the enzyme pathway• normalizing mangled blood vessels• preventing the switch from turning on
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Vascular endothelial growth factor VEGF
One of the most specific and critical regulators of angiogenesis
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VEGF functions VEGF functions on eon enndothelialdothelial cellscells
Function MechanismProliferation Activation of mitogen-activated
protein kinasesPermeability Vesicovascular organelles;
endothelial fenestrations; opening of junctions between adjacent endothelial cells
Invasion Induction of metalloproteinases uPA, uPAR, TTPA
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VEGF functions VEGF functions on eon enndothelialdothelial cellscells
Function MechanismMigration Activation of FAK, p38, nitric oxideSurvival Induction of PI3K/Akt, Bcl2, A1,
survivin, XIAP or FAK; inhibition of capases
Activation Up-regulation of integrin expression; alteration is cell cytoskeleton
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Binding specificity of various VEGF family members and their receptors (VEGFR)
Hicklin D.J., Ellis L.M.: Role of the Vascular Endothelial Growth Factor pathwayin the tumor growth and angiogenesis. J. Clin. Oncol., 2005, 23, 1011-1027.
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Tumor expression of VEGF correlates with tumor
invasiveness and prognosisin patients with cancer
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Excessive expression of VEGFExcessive expression of VEGF in in human malignancieshuman malignancies
Cancer type Tumours (%) Correlations
Non-small-cell lung
45 - 55
Colorectal 40 - 60Recurrence, survival
Breast 30 - 60 Vascular density, relapse-free survival, overall survival
Prostate 30 Vascular density, relapse-free survival
Renal 30 - 100 Vascular density
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Over expression of VEGF mRNA in human malignancies
• intracranial tumour• thyroid tumour• lung cancer• breast cancer• gastrointestinal tract tumour• urinary tract tumour• female reproductive tract tumour• angiosarcoma
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Relationship between VEGF expression and metastasis in colon cancer patients
Ellis L.M., Takahashi Y., Liu W., Shaheen R.M.: Vascular endothelial growthfactor in human colon cancer: biology and therapeutic implication. Oncologist, 2000, 5, 11-15.
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Relationship between vessel count and metastasis in colon cancer patients
Ellis L.M., Takahashi Y., Liu W., Shaheen R.M.: Vascular endothelial growthfactor in human colon cancer: biology and therapeutic implication. Oncologist, 2000, 5, 11-15.
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Kaplan-Meier curves for vessel count expression in colon cancer patients
Ellis L.M., Takahashi Y., Liu W., Shaheen R.M.: Vascular endothelial growthfactor in human colon cancer: biology and therapeutic implication. Oncologist, 2000, 5, 11-15.
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Kaplan-Meier curves for VEGF expression in colon cancer patients
Ellis L.M., Takahashi Y., Liu W., Shaheen R.M.: Vascular endothelial growthfactor in human colon cancer: biology and therapeutic implication. Oncologist, 2000, 5, 11-15.
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BevacizumabAvastin
• monoclonal antibody • signal-blocking angiogenesis inhibitor• intercepts a tumor’s VEGF signals and
stops them from connecting with the endothelial cells
• is used in colon cancer therapy
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Bevacizumab pharmacokinetics
• linear pharmacokinetics• therapeutic plasma concentration
10-30 µg/ml• terminal elimination half-life time1-2 weeks
Optimal dose and schedule depend on tumour type
• dose 5-15 mg/kg• schedule every 2-3 weeks
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Yang J.C., Haworth L., Sherry R.M. Hwu P.: A randomized trial ofbevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med.., 2003, 349, 427-434.
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Bevacizumab clinical trials in solid tumors
• breast cancer• non-small cell lung
cancer• colorectal cancer• rectal cancer• renal cell carcinoma • hepatocellular
cancer• pancreatic cancer
• soft- tissue sarcoma• Kaposi’s sarcoma• mesothelioma• head and neck• melanoma• carcinoid carcinoma• prostate• ovarian cancer• cervical cancer
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Bevacizumab clinical trials in hematologic malignancies
• myelodysplastic syndrome• non-Hodgkin lymphoma • acute myeloid leukemia• chronic myeloid leukemia• multiple myeloma
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Bevacizumab phase II clinical trials efficacy results in patients with metastatic breast
cancerOutcome 3 mg/kg 10 mg/kg 20 mg/kg TotalTotal
n 18 41 16 7575
Response rate (%) 1 (5.6) 3 (7.3) 1 (6.3) 5 (6.5 (6.77))
Median response duration (month) 3.1 5.6 8.0 5.65.6
Stable disease or better at day 154 (%)
2 (11) 7 (17) 3 (19) 12 (16)12 (16)
Median survival (month) 14.0 12.8 7.6 10.210.2
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Combination of the antibody with standard chemotherapy and
radiotherapy regimen significantly prolonged time of
progression and increasesurvival than chemotherapy alone
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Angiogenesis inhibitors
1. Mechanism of action is cytostatic (causing arrest of cell division, not cell death).
2. Objective response is not a decision-making surrogate end point.
3. Chronic administration is required to demonstrate activity.
4. Cytotoxic chemotherapy is not viewed as competition but as a potential partner in therapeutic effect.
5. Importance of tumor cell burden and resistance may be less than with cytotoxics.
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Angiogenesis inhibitors
1. Target: endothelial cell receptors.
2. Resistance may not be important, as the target is a normal host cell.
3. Hypoxia and cell kinetics may not be important; role of tumor cell burden to be determined.
Cytotoxic therapy
1. Target: tumor cells.
2. Resistance is a major factor.
3. Hypoxia, cell kinetics, and tumor cell burden are critical factors.
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Combining cytotoxic agents and angiogenesis inhibitors
1. Cellular targets are different, with both pathways likely to result in decreased tumor burden.
2. Resistance patterns should not overlap.3. Lack of myelosupression with
angiogenesis inhibitors enables full doses of both agents to be administered.
4. Assumption of additive effects is reasonable.
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Efficacy of bevacizumab (BEV) when added to carboplatin/paclitaxel (CP) in patients with locally
advanced or metastatic NSCLC
OutcomeCP alone
(n=32)CP + BEV 7.5 mg/kg
(n=32)
CP + BEV 15 mg/kg
(n=34)Response rate (%)
18.8 28.1 31.5
TTP (months [range])
4.2 (0-12.6)
4.3 (0.2-12.9)
7.4 (0.7-12.5)*
Mean survival (month)
14.9 11.6 17.7
p = 0.02
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Results of phase II controlled study of bevacizumabin patients with metastatic colorectal cancer
Fluorouracil, leucovorin, and bevacizumab
Outcome
Fluorouracil plus
leucovorin(n=36) 5 mg/kg
(n=35)10 mg/kg
(n=35)
Response rate (%) 6 (17) 14 (40)* 8 (24)
Median time to disease progression (month)
5.2 9.0** 7.2
Median survival (month)
13.8 21.5 16.1
* p = 0.029 ** p = 0.005
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Results of phase III trial of first-line Irinotecan, fluorouracil and leucovorin with or without bevacizumab
in patients with metastatic colorectal cancer
OutcomeIFL + placebo
(n=412)IFL + bevacizumab
(n=403)
Response rate (%) 35 45*
Median time to disease progression (month)
7.1 10.4**
Median progression-free survival (month)
6.2 10.6***
Median survival (month)
15.6 20.3****
* p=0.0029, **p=0.0014, ***p<0.00001, ****p=0.00003
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Main adverse events associated with bevacizumab plus carboplatin/paclitaxel in
patients with advanced or metastatic NSCLC
CP alone CP + BEV 7.5 mg/kg
CP + BEV 15 mg/kg
All G 3/4 All G 3/4 All G 3/4Fever 4 0 11 2 11 2Hypertension 1 1 5 0 6 2Bleeding 0 0 4 2 0 0Diarrhea 6 0 9 3 14 1Leucopenia 10 7 15 10 19 13Epistaxis 2 0 10 0 15 0Hemoptysis 2 0 9 3 4 1
Adverse event
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Frequency of adverse effects in a phase II controlled study of bevacizumab in patients with
metastatic colorectal cancer
5-FU/LV + bevacizumab5-FU/LV
5 mg/kg 10 mg/kgAll G 3/4 All G 3/4 All G 3/4
Any event 35 19 35 26 32 25Diarrhea 29 13 32 10 24 10Leucopenia 1 1 4 2 1 1Stomatitis 6 0 8 0 6 0Fever 4 0 13 0 11 1Headache 5 0 11 0 12 1Rash 7 0 16 1 11 0Chills 1 0 5 0 5
Adverse event
0
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Frequency of adverse effects in a phase II controlled study of bevacizumab in patients with
metastatic colorectal cancer
5-FU/LV + bevacizumab5-FU/LV
5 mg/kg 10 mg/kgAll G 3/4 All G 3/4 All G 3/4
Abdominal pain 19 1 16 3 15 4Weight loss 8 0 5 1 3 0GI hemorrhage 0 0 2 0 5 3Epistaxis 4 0 16 0 17 0Hypertension 1 0 4 3 9 8Infection 7 0 14 0 8 1Trombotic events 3 1 9 5 4
Adverse event
2
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Frequency of adverse effects in a phase III trials of first-line irinotecan, fluorouracil, and leucovorin with or without bevacizumab in patients with metastatic colorectal cancer
%Adverse effect IFN + placebo
(n=412)IFN + bevacizumab
(n=403)Grade 3 or 4 bleeding 2.5 3.1
Any tromboembolism 16.1 19.3
Grade 3 hypertension 2.3 10.9
Grade 3 proteinuria 0.8 0.8
Gastrointestinal perforation 0.0 1.5
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VEGF/VEGFR inhibitors under investigation
Hicklin D.J., Ellis L.M.: Role of the Vascular Endothelial Growth Factor pathwayin the tumor growth and angiogenesis. J. Clin. Oncol., 2005, 23, 1011-1027.
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AZD2171 Recentin
• significantly reduce the size of glioblastomas
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Sorafenib, sunitinib
• inhibition of receptor tyrosine kinaseactivity
• are used in renal cell carcinoma
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Thalidomide
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Normalization of tumor vasculature following anti-VEGFR-2 therapy
Hicklin D.J., Ellis L.M.: Role of the Vascular Endothelial Growth Factor pathway in the tumor growth and angiogenesis. J. Clin. Oncol., 2005, 23, 1011-1027.
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Other possibility is the therapy withendogenous inhibitors of
angiogenesis, such endostatin and angiostatin
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Other angiogenesis inhibitorsOther angiogenesis inhibitorsin phase II/III in phase II/III clinical trialsclinical trials
Agent MechanismAngiozyme Ribozyme
Endostatin Induction of endothelial cell apoptosis
Neovastat Matrix metalloproteasesinhibitor
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AngiopoietinAngiopoietin role in the role in the formation of new vesselsformation of new vessels
Angiopoietin 2Angiopoietin 1• endothelial cell (EC)
sprouting• vessel stabilization
• EC migration• EC proliferation• EC spouting only in the
presence of VEGF• vessel destabilization by
antagonizing angiopoietin 1 signaling
• ↑ EC apoptosis
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The interaction relation between VEGF and angiopoietins in the development of tumor angiogenesis
Huang Z., Bao S.D.: Roles of main pro- and anti-angiogenic factors in tumorangiogenesis. World J. Gastroenterol., 2004, 10, 463-470.
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Some anticancer drugs e.g. paclitaxeland cyclophosphamide have been
found to interfere with angiogenesis, though they were not originally
developed for that reason
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Plants with Plants with antiangiogenicantiangiogenic activityactivity
Plants Antiangiogenic effects
Green tee extract Inhibits in vitro and in vivotumor angiogenesis
Soy phytochemicalconcentrate
Inhibits angiogenesis in prostate and bladder carcinoma xenograf
Viscum album coloratum(aquous extract)
Inhibits lung tumorangiogenesis and metastatis
Polypodium leucotomos(extract)
Inhibits number of blood vessels in UVB- irradiated mouse skin
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PhytochemicalsPhytochemicalswith with antiantiangiogenicangiogenic activityactivity
Phytochemicals Antiangiogenic effectsSilymarin / silibin Inhibits VEGF and MMP-2 secretion,
growth and tube formationEpicatechin / Epigallocatechin
Inhibits VEGF transcription and production, increases apoptotic death of endothelial cells
Curcumin Inhibits microvessels densityResveratol Inhibits angiogenesis, metastatis and
tube formationQuercetin Inhibits endothelial cells proliferation,
migration and tube formationHydroxyflavone Inhibits in vitro angiogenesis
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Dziękuję bardzo za uwagę☺
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