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Vascular Disruption andVascular Disruption andVascular Disruption and Vascular Disruption and AntiangiogenesisAntiangiogenesis

Dietmar W. Siemann, Ph.D.Dietmar W. Siemann, Ph.D.University of FloridaUniversity of FloridaUniversity of FloridaUniversity of Florida

Vascular Disruption and AntiangiogenesisVascular Disruption and Antiangiogenesis

Wh D C Th i F il?Wh D C Th i F il?Why Do Cancer Therapies Fail?Why Do Cancer Therapies Fail?

•• Both Both local recurrenceslocal recurrences and and distant metastasesdistant metastasesare significantly affected by tumor are significantly affected by tumor progressionprogressionand tumorand tumor pathophysiologypathophysiologyand tumor and tumor pathophysiologypathophysiology..

•• These factors are critically impacted by the These factors are critically impacted by the initiationinitiation andand maintenance/expansionmaintenance/expansion of aof a tumortumorinitiationinitiation and and maintenance/expansionmaintenance/expansion of a of a tumor tumor blood vessel networkblood vessel network..

Vascular Disruption and AntiangiogenesisVascular Disruption and AntiangiogenesisMaintenance Maintenance

and and E iE iExpansionExpansion

InitiationInitiationInitiationInitiation


Hypoxia and acidity are inducers Hypoxia and acidity are inducers

endostatinendostatinangiostatinangiostatin

VEGFVEGFPDGFPDGF

of angiogenic signalingof angiogenic signaling

angiostatinangiostatininterferonsinterferonsothersothers

PDGFPDGFFGFFGFILIL--88othersothers

B lB lBalanceBalance


proangiogenic factors outweigh proangiogenic factors outweigh i i i fi i i f

endostatinendostatinangiostatinangiostatini t fi t f

antiangiogenic factorsantiangiogenic factors

interferonsinterferonsothersothers VEGFVEGF

PDGFPDGFFGFFGFILIL 88ILIL--88othersothers

New vessel developmentNew vessel development

•• VEGF is considered the most powerful proangiogenic factor in tumorsVEGF is considered the most powerful proangiogenic factor in tumors•• Associated with tumor growth rate, vessel density, metastasesAssociated with tumor growth rate, vessel density, metastases


Inhibition of VEGF signalingInhibition of VEGF signalingInhibition of VEGF signalingInhibition of VEGF signaling

AntiAnti--VEGF antibodiesVEGF antibodies(Bevacizumab)(Bevacizumab)

VEGF-AVEGF CVEGF-CVEGF-D

P

Extracellular environment

PP

VEGFR-2

Tyrosine kinase Tyrosine kinase inhibitors inhibitors (Sorafenib, (Sorafenib, Vandetanib,Vandetanib,

Intracellular environment

Vandetanib, Vandetanib, Cediranib, Cediranib, Brivanib)Brivanib)Endothelial cell


•• Inhibitors of VEGFInhibitors of VEGF--associated signaling demonstrate associated signaling demonstrate antitumor efficacy in a wide variety of rodent tumor models antitumor efficacy in a wide variety of rodent tumor models and human tumor xenografts including renal, colorectal, KS, and human tumor xenografts including renal, colorectal, KS, and sarcoma.and sarcoma.

30

s)

Caki-1

Median

20

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ize

(day

s

17

25-75%10-90%

10

to 5

x in

itia

8.5

14

0

Tim

e

Treatment: daily (M-F) x 2

Control BMS58266450 mg/kg

BMS582664100 mg/kg

Treatment


•• But But –– antianti--angiogenic therapy efficacy in solid tumors has angiogenic therapy efficacy in solid tumors has b d tb d t dd h th i lik l t li i th th i lik l t li i tbeen modest been modest –– and and –– such therapies are unlikely to eliminate such therapies are unlikely to eliminate the entire tumor cell population on their own.the entire tumor cell population on their own.

811 untreated metastatic colorectal811 untreated metastatic colorectal

Hurvitz et al, 2004Hurvitz et al, 2004

••811 untreated metastatic colorectal 811 untreated metastatic colorectal cancer patientscancer patients

••randomized to IFL +/randomized to IFL +/-- bevacizumabbevacizumab

•• Primary endpoint = overall survivalPrimary endpoint = overall survival

••Secondary endpoint = progression Secondary endpoint = progression free survival response ratefree survival response ratefree survival, response ratefree survival, response rate


xxTarget the Target the

xxxxxx

xxggangiogenesis angiogenesis

processprocess

xx xxxx

xx

xx

Target the Target the existing vessel existing vessel

networknetworkxx

xx

•• Biologic basedBiologic based•• Small molecule drugs Small molecule drugs

–– shortshort--lived tubulin depolymerizing agentslived tubulin depolymerizing agents


V l Di ti A tV l Di ti A tVascular Disrupting AgentsVascular Disrupting Agentselicit a tumor cell death cascade due to prolonged ischemiaelicit a tumor cell death cascade due to prolonged ischemia

Shape change and detachment

VE-cadherin disengagement

TumorTumor Damage toDamage to Vessel occlusionVessel occlusionneovasculatureneovasculature

ggestablished vesselestablished vessel and tumor necrosisand tumor necrosis


VDA T t t EffiVDA T t t EffiVDA Treatment EfficacyVDA Treatment EfficacyControl VDA treated

•• Vascular disrupting Vascular disrupting agents effectively agents effectively eliminate large areas eliminate large areas ggof solid tumors.of solid tumors.

•• Particularly areasParticularly areas•• Particularly areas Particularly areas typically resistant to typically resistant to conventional anticonventional anti--cancer therapies.cancer therapies.cancer therapies.cancer therapies.


•• But But –– cells surviving at the tumor periphery aggressively promote cells surviving at the tumor periphery aggressively promote l i til i ti dd h th i lik l t li i th th i lik l t li i tneovascularization neovascularization –– and and –– such therapies are unlikely to eliminate such therapies are unlikely to eliminate

the entire tumor cell population on their own.the entire tumor cell population on their own.


C bi i V l Di t d St t iC bi i V l Di t d St t iCombining Vessel Directed StrategiesCombining Vessel Directed Strategies

•• VDAs effectively VDAs effectively eliminate large areas eliminate large areas of tumorsof tumors 0.8

1.0

y

ControlZD6474ZD6126

•• Cells surviving VDA Cells surviving VDA treatment treatment aggressively promoteaggressively promote

0.6al

pro

babi

lity ZD6474 + ZD6126

aggressively promote aggressively promote neovascularizationneovascularization

•• VDAs plus AIsVDAs plus AIs0.2

0.4

Surv

iva

•• VDAs plus AIs VDAs plus AIs provide more provide more effective tumor effective tumor therapy than either therapy than either

0 20 40 60 80 100 120

Time (days)

0.0KSY-1

treatment alonetreatment alone

Siemann and Shi,Siemann and Shi, IJROBPIJROBP, 2004, 2004


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( day

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Tim

eto

5

6

14.512

Control Bevacizumab CA4P OXi4503 + BevBev +0

T 6

BevBevCA4P OXi4503

Treatment


C l iC l iConclusionConclusion

•• Therapeutic strategies relying on single biologic Therapeutic strategies relying on single biologic agent targeting approaches may be beneficial but agent targeting approaches may be beneficial but their ultimate impact on treatment efficacy is likelytheir ultimate impact on treatment efficacy is likelytheir ultimate impact on treatment efficacy is likely their ultimate impact on treatment efficacy is likely to be limited. to be limited.

•• AIs and VDAs can modify conventional antiAIs and VDAs can modify conventional anti--cancercancerAIs and VDAs can modify conventional antiAIs and VDAs can modify conventional anti cancer cancer therapy therapy –– but better cytotoxics are needed.but better cytotoxics are needed.

•• The application of combined The application of combined Biologic Targeting Biologic Targeting StrategiesStrategies needs to be considered.needs to be considered.


Si l P thSi l P thSingle PathwaySingle Pathway

•• Multiple intervention pointsMultiple intervention points

Immuneff

Anti-ligand mAbs

effector cell

BispecificAbs

Ligand/toxin conjugate

Anti-receptormAbs

TKsignal•• Combinations Combinations

targetingtargetingLigandLigand

Nucleus XX–– LigandLigand–– ReceptorReceptor–– TK signalTK signal

Antisense

gg–– MessageMessage


Si l P th T ti CSi l P th T ti CSingle Pathway Targeting ConcernsSingle Pathway Targeting Concerns

•• The complexity of neovascularization pathways The complexity of neovascularization pathways implies that disrupting only a single aspect of implies that disrupting only a single aspect of angiogenesis probably will not sufficeangiogenesis probably will not sufficeangiogenesis probably will not suffice.angiogenesis probably will not suffice.

•• Multiple RTKs are coMultiple RTKs are co activated in tumors andactivated in tumors and•• Multiple RTKs are coMultiple RTKs are co--activated in tumors and activated in tumors and redundant inputs drive and maintain redundant inputs drive and maintain downstream signaling, thereby limiting the downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs.efficacy of therapies targeting single RTKs.


M lti l P th T tiM lti l P th T tiMultiple Pathway TargetingMultiple Pathway Targeting

•• Possible StrategiesPossible Strategies–– Single molecule affecting several pathways Single molecule affecting several pathways

•• Sunitinib (PDGF, VEGF, other RTKs)Sunitinib (PDGF, VEGF, other RTKs)•• Sorafenib (Raf, PDGF, VEGF, cKit)Sorafenib (Raf, PDGF, VEGF, cKit)•• Vandetanib (VEGF, EGF)Vandetanib (VEGF, EGF)

–– Individual agents for individual pathwaysIndividual agents for individual pathways


T ti F ti ll R l t d P thT ti F ti ll R l t d P thTargeting Functionally Related PathwaysTargeting Functionally Related Pathways

•• ProgressionProgression–– Proliferation (EGF Proliferation (EGF –– Cetuximab, TKIs; mTOR Cetuximab, TKIs; mTOR

RAD001 T i li )RAD001 T i li )–– RAD001, Temsirolimus)RAD001, Temsirolimus)–– Vasculature (VDAs, AIs)Vasculature (VDAs, AIs)

•• MetastasesMetastasesA i i (VEGFA i i (VEGF i TKI ‘ ib ’)i TKI ‘ ib ’)–– Angiogenesis (VEGF Angiogenesis (VEGF –– various TKI ‘nibs’)various TKI ‘nibs’)

–– Invasion (Invasion (SrcSrc –– AZD0530, Dasatinib)AZD0530, Dasatinib)


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40

50

60

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ZD6474

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20.1

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Control 25 mg/kg 50 mg/kg

Treatment

0

10

25

30

35

40

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24

Treatment

•• Combining strategies Combining strategies

10

15

20

25N

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un 24

1714.5

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g gg gthat target angiogenesis that target angiogenesis and cell invasion may and cell invasion may inhibit metastases inhibit metastases formationformation

Control ZD647425 mg/kg

AZ053010 mg/kg

ZD6474+ AZD0530

Treatment

0

5formation.formation.


C l iC l iConclusionsConclusions

•• Future therapeutic strategies should seek to Future therapeutic strategies should seek to develop “combination biologic therapy” develop “combination biologic therapy” targeting multiple intervention points and/ortargeting multiple intervention points and/ortargeting multiple intervention points and/or targeting multiple intervention points and/or functionally related pathways.functionally related pathways.

•• AndAnd –– to apply such combinations of biologic to apply such combinations of biologic agents in conjunction with conventional agents in conjunction with conventional anticancer treatments.anticancer treatments.

vascular disruption andvascular disruption and antiangiogenesis slides/0930 siemann... ·...

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