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Vascular Disruption and Vascular Disruption and Vascular Disruption and Vascular Disruption and Antiangiogenesis Antiangiogenesis

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

Vascular Disruption and Antiangiogenesis Vascular 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 recurrences local recurrences and and distant metastases distant metastases are significantly affected by tumor are significantly affected by tumor progression progression and tumor and tumor pathophysiology pathophysiology and tumor and tumor pathophysiology pathophysiology.

• These factors are critically impacted by the

These factors are critically impacted by the initiation initiation and and maintenance/expansion maintenance/expansion of a

• f a tumor

tumor initiation initiation and and maintenance/expansion maintenance/expansion of a

• f a tumor

tumor blood vessel network blood vessel network.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

Maintenance Maintenance and and E i E i Expansion Expansion Initiation Initiation Initiation Initiation

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

Hypoxia and acidity are inducers Hypoxia and acidity are inducers endostatin endostatin angiostatin angiostatin VEGF VEGF PDGF PDGF

• f angiogenic signaling
• f angiogenic signaling

angiostatin angiostatin interferons interferons

• thers
• thers

PDGF PDGF FGF FGF IL IL-

• 8

8

• thers
• thers

B l B l Balance Balance

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

proangiogenic factors outweigh proangiogenic factors outweigh i i i f i i i f endostatin endostatin angiostatin angiostatin i t f i t f antiangiogenic factors antiangiogenic factors interferons interferons

• thers
• thers

VEGF VEGF PDGF PDGF FGF FGF IL IL 8 IL IL-8

• thers
• thers

New vessel development New vessel development

• VEGF is considered the most powerful proangiogenic factor in tumors

VEGF is considered the most powerful proangiogenic factor in tumors

• Associated with tumor growth rate, vessel density, metastases

Associated with tumor growth rate, vessel density, metastases

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

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

Anti Anti-

• VEGF antibodies

VEGF antibodies (Bevacizumab) (Bevacizumab) VEGF-A VEGF C VEGF-C VEGF-D P Extracellular environment P P VEGFR-2 Tyrosine kinase Tyrosine kinase inhibitors inhibitors (Sorafenib, (Sorafenib, Vandetanib, Vandetanib, Intracellular environment Vandetanib, Vandetanib, Cediranib, Cediranib, Brivanib) Brivanib) Endothelial cell

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

• Inhibitors of VEGF

Inhibitors 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

al size (days

17 25-75% 10-90%

10

to 5x initia

8.5 14

Time

Treatment: daily (M-F) x 2

Control BMS582664 50 mg/kg BMS582664 100 mg/kg

Treatment

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

• But

But – – anti anti-

• angiogenic therapy efficacy in solid tumors has

angiogenic therapy efficacy in solid tumors has b d t b d t d h th i lik l t li i t h th i lik l t li i t been 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 colorectal 811 untreated metastatic colorectal Hurvitz et al, 2004 Hurvitz et al, 2004

• 811 untreated metastatic colorectal

811 untreated metastatic colorectal cancer patients cancer patients

• randomized to IFL +/

randomized to IFL +/-

• bevacizumab

bevacizumab

• Primary endpoint = overall survival

Primary endpoint = overall survival

• Secondary endpoint = progression

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

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

x Target the Target the x x x x g angiogenesis angiogenesis process process x x x x x Target the Target the existing vessel existing vessel network network x x

• Biologic based

Biologic based

• Small molecule drugs

Small molecule drugs

–

short short-

• lived tubulin depolymerizing agents

lived tubulin depolymerizing agents

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

V l Di ti A t V l Di ti A t Vascular Disrupting Agents Vascular Disrupting Agents

elicit a tumor cell death cascade due to prolonged ischemia elicit a tumor cell death cascade due to prolonged ischemia

Shape change and detachment VE-cadherin disengagement

Tumor Tumor Damage to Damage to Vessel occlusion Vessel occlusion neovasculature neovasculature g established vessel established vessel and tumor necrosis and tumor necrosis

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

VDA T t t Effi VDA T t t Effi VDA Treatment Efficacy VDA Treatment Efficacy

Control VDA treated

• Vascular disrupting

Vascular disrupting agents effectively agents effectively eliminate large areas eliminate large areas g

• f solid tumors.
• f solid tumors.
• Particularly areas

Particularly areas

• Particularly areas

Particularly areas typically resistant to typically resistant to conventional anti conventional anti-

• cancer therapies.

cancer therapies. cancer therapies. cancer therapies.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

• But

But – – cells surviving at the tumor periphery aggressively promote cells surviving at the tumor periphery aggressively promote l i ti l i ti d h th i lik l t li i t h th i lik l t li i t neovascularization 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.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

C bi i V l Di t d St t i C bi i V l Di t d St t i Combining Vessel Directed Strategies Combining Vessel Directed Strategies

• VDAs effectively

VDAs effectively eliminate large areas eliminate large areas

• f tumors
• f tumors

0.8 1.0

y

Control ZD6474 ZD6126

• Cells surviving VDA

Cells surviving VDA treatment treatment aggressively promote aggressively promote

0.6

al probability

ZD6474 + ZD6126

aggressively promote aggressively promote neovascularization neovascularization

• VDAs plus AIs

VDAs plus AIs

0.2 0.4

Surviva

• VDAs plus AIs

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

20 40 60 80 100 120

Time (days)

0.0

KSY-1

treatment alone treatment alone

Siemann and Shi, Siemann and Shi, IJROBP IJROBP, 2004 , 2004

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

40

ys)

30

size (day

24 33

20

5x initial s

24 19

10

Time to 5

6 14.5 12 Control Bevacizumab CA4P OXi4503 + Bev Bev +

T

6 Bev Bev CA4P OXi4503

Treatment

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

C l i C l i Conclusion Conclusion

• 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 likely their ultimate impact on treatment efficacy is likely their 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 anti

AIs and VDAs can modify conventional anti-cancer cancer AIs and VDAs can modify conventional anti AIs 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 Strategies Strategies needs to be considered. needs to be considered.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

Si l P th Si l P th Single Pathway Single Pathway

• Multiple intervention points

Multiple intervention points

Immune ff Anti-ligand mAbs effector cell Bispecific Abs Ligand/toxin conjugate Anti-receptor mAbs TK signal

• Combinations

Combinations targeting targeting

Ligand Ligand

Nucleus

X

– Ligand Ligand – Receptor Receptor – TK signal TK signal

Antisense

g – Message Message

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

Si l P th T ti C Si l P th T ti C Single Pathway Targeting Concerns Single 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 suffice angiogenesis probably will not suffice angiogenesis probably will not suffice. angiogenesis probably will not suffice.

• Multiple RTKs are co

Multiple RTKs are co activated in tumors and activated in tumors and

• Multiple RTKs are co

Multiple 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.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

M lti l P th T ti M lti l P th T ti Multiple Pathway Targeting Multiple Pathway Targeting

• Possible Strategies

Possible 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 pathways Individual agents for individual pathways

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

T ti F ti ll R l t d P th T ti F ti ll R l t d P th Targeting Functionally Related Pathways Targeting Functionally Related Pathways

• Progression

Progression – 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)

• Metastases

Metastases A i i (VEGF A i i (VEGF i TKI ‘ ib ’) i TKI ‘ ib ’) – Angiogenesis (VEGF Angiogenesis (VEGF – – various TKI ‘nibs’) various TKI ‘nibs’) – Invasion ( Invasion (Src Src – – AZD0530, Dasatinib) AZD0530, Dasatinib)

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

60 40 50 60

ber

37.1 ZD6474

20 30

Vessel num

37.1 32 20.1

45 KHT sarcoma Control 25 mg/kg 50 mg/kg

Treatment

10 25 30 35 40

ng Colonies

24

Treatment

• Combining strategies

Combining strategies

10 15 20 25

Number of Lun

24 17 14.5 10

g g g g that target angiogenesis that target angiogenesis and cell invasion may and cell invasion may inhibit metastases inhibit metastases formation formation

Control ZD6474 25 mg/kg AZ0530 10 mg/kg ZD6474 + AZD0530

Treatment

5

formation. formation.

Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis

C l i C l i Conclusions Conclusions

• 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/or targeting multiple intervention points and/or targeting multiple intervention points and/or targeting multiple intervention points and/or functionally related pathways. functionally related pathways.

• And

And – 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.