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 Why Do Cancer Therapies Fail? Why Do Cancer Therapies Fail? Wh D D C C Th Th i i F il? F il? • 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 and tumor pathophysiology and tumor pathophysiology pathophysiology pathophysiology. • These factors are critically impacted by the These factors are critically impacted by the initiation and initiation initiation and initiation and maintenance/expansion and maintenance/expansion maintenance/expansion of a maintenance/expansion of a of a tumor of a tumor tumor tumor blood vessel network blood vessel network .
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis Maintenance Maintenance and and E E Expansion Expansion i i Initiation Initiation Initiation Initiation
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis Hypoxia and acidity are inducers Hypoxia and acidity are inducers of angiogenic signaling of angiogenic signaling VEGF VEGF endostatin endostatin PDGF PDGF PDGF PDGF angiostatin angiostatin angiostatin angiostatin FGF FGF interferons interferons IL IL- -8 8 others others others others B l B l Balance Balance
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis proangiogenic factors outweigh proangiogenic factors outweigh antiangiogenic factors antiangiogenic factors i i i i i i f f endostatin endostatin angiostatin angiostatin interferons interferons i t i t f f VEGF VEGF others others PDGF PDGF FGF FGF IL-8 IL IL IL 8 others others 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 Extracellular environment P Tyrosine kinase Tyrosine kinase Intracellular P P inhibitors inhibitors environment (Sorafenib, (Sorafenib, VEGFR-2 Vandetanib, Vandetanib, 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 Caki-1 s) Median al size (days 25-75% 10-90% 20 17 to 5x initia 14 10 8.5 Time Treatment: daily (M-F) x 2 0 Control BMS582664 BMS582664 50 mg/kg 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 been modest – b been modest d d t t – and and – d – such therapies are unlikely to eliminate such therapies are unlikely to eliminate h th h th i i lik l lik l t t li li i i t t the entire tumor cell population on their own. the entire tumor cell population on their own. Hurvitz et al, 2004 Hurvitz et al, 2004 • 811 untreated metastatic colorectal 811 untreated metastatic colorectal 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 Target the Target the g x x angiogenesis angiogenesis process process x x x x Target the Target the x x existing vessel existing vessel x network network x 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 V Vascular Disrupting Agents Vascular Disrupting Agents l l Di Di ti ti A A t t elicit a tumor cell death cascade due to prolonged ischemia elicit a tumor cell death cascade due to prolonged ischemia Shape change and VE-cadherin detachment disengagement Tumor Tumor Damage to Damage to g Vessel occlusion Vessel occlusion neovasculature neovasculature established vessel established vessel and tumor necrosis and tumor necrosis
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis VDA T VDA T VDA Treatment Efficacy VDA Treatment Efficacy t t t Effi t Effi Control VDA treated • Vascular disrupting Vascular disrupting agents effectively agents effectively eliminate large areas eliminate large areas g of solid tumors. of 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 neovascularization neovascularization – l l i i ti ti – and and – d – such therapies are unlikely to eliminate such therapies are unlikely to eliminate h th h th i i lik l lik l t t li li i i t t 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 Combining Vessel Directed Strategies Combining Vessel Directed Strategies C bi i bi i V V l Di l Di t d St t d St t t i i • VDAs effectively VDAs effectively 1.0 eliminate large areas eliminate large areas Control of tumors of tumors ZD6474 0.8 ZD6126 y al probability ZD6474 + ZD6126 • Cells surviving VDA Cells surviving VDA 0.6 treatment treatment aggressively promote aggressively promote aggressively promote aggressively promote Surviva 0.4 neovascularization neovascularization 0.2 • VDAs plus AIs • VDAs plus AIs VDAs plus AIs VDAs plus AIs KSY-1 provide more provide more 0.0 effective tumor effective tumor 0 20 40 60 80 100 120 therapy than either therapy than either Time (days) treatment alone treatment alone Siemann and Shi, Siemann and Shi, IJROBP IJROBP , 2004 , 2004
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis 40 ys) size (day 33 30 5x initial s 24 24 20 19 Time to 5 14.5 12 10 T 6 6 0 Bev Bev Control Bevacizumab CA4P OXi4503 + Bev Bev + CA4P OXi4503 Treatment
Vascular Disruption and Antiangiogenesis Vascular Disruption and Antiangiogenesis C Conclusion Conclusion C l l i i • 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 AIs and VDAs can modify conventional anti AIs and VDAs can modify conventional anti cancer 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 Si Single Pathway Single Pathway l l P th P th • Multiple intervention points Multiple intervention points Anti-ligand Immune mAbs effector ff cell Ligand/toxin Bispecific conjugate Abs TK • Combinations Combinations Anti-receptor signal mAbs targeting targeting – Ligand Ligand Ligand Ligand X – Receptor Receptor Nucleus – TK signal TK signal g – Message Message Antisense
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