Angiogenesis: Using Old and New Approaches .

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John Mackey, MD Professor of Oncology University of Alberta Edmonton, Canada. Angiogenesis: Using Old and New Approaches. Faculty Disclosure. John R. Mackey, MD, FRCP (C), has disclosed that he has received consulting fees from Eli Lilly and Roche and CME honoraria from Amgen. Overview.
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John Mackey, MD Professor of Oncology University of Alberta Edmonton, Canada Angiogenesis: Using Old and New Approaches

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Faculty Disclosure John R. Mackey, MD, FRCP (C), has revealed that he has gotten counseling charges from Eli Lilly and Roche and CME honoraria from Amgen.

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Overview Angiogenesis and the VEGF/VEGF-R pathway New systems and new operators The metastatic/adjuvant bay Toward prescient biomarkers

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Angiogenesis Physiologic procedure of fresh recruits vessel arrangement Principally determined by collaborations between vascular endothelial development components and 3 high-liking VEGF receptors Folkman J. Semin Oncol. 2002;29(suppl 6):15-18. Hicklin DJ, et al. J Clin Oncol. 2005;23:1011-1027.

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VEGF Family of Ligands and Receptors VEGF-A 121 VEGF-A 145 VEGF-A 165 VEGF-A 189 VEGF-A 206 VEGF-B 167 VEGF-B 186 PlGF-1,2 VEGF-C VEGF-D VEGF-E Y s-s NRP-1 NRP-2 VEGFR-1 (Flt-1) VEGFR-2 (Flk-1/KDR) VEGFR-3 (Flt-4) Vasculogenesis Angiogenesis Lymphangiogenesis

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An Obvious Target . . .

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P Agents Targeting the VEGF Pathway VEGF-An Anti-VEGFR2 antibodies (ramucirumab) Anti-VEGF antibodies (bevacizumab) Soluble VEGF receptors (aflibercept) VEGFR-1 VEGFR-2 VEGFR-3 Endothelial cell Agents in yellow = FDA affirmed Small-particle inhibitors of VEGFR (PTK-787, AZD2171, motesanib, sunitinib, sorafenib, pazopanib, axitinib, others)

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Agents Targeting the VEGF Pathway Small-atom VEGFR inhibitors Vatalanib (PTK787) AZD2171 Sunitinib (SU11248) Sorafenib (BAY 43-9006) Motesanib (AMG 706) Pazopanib AG-013736 Others Anti-VEGF antibodies Bevacizumab Anti–VEGFR-2 antibodies Ramucirumab (IMC-1121B) Soluble VEGF receptors Aflibercept (VEGF Trap)

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Antiangiogenic Risk:Benefit Ratio Efficacy Toxicity

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Antiangiogenic Class Toxicities Hypertension Clotting Bleeding Congestive heart disappointment (when joined with anthracyclines) Financial Agent-particular toxicities Motesanib: cholecystitis Pigmentation changes: sunitinib, pazopanib Gressett SM, et al. Ann Pharmacother. 2009;43:490-501. Blumenschein GR Jr, et al. Ann Oncol. 2011;[Epub in front of print]. Rosenbaum SE, et al. Bolster Care Cancer. 2008;16:557-566. Book of scriptures KC, et al. Lancet Oncol. 2010;11:962-972.

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Therapeutic Efficacy Modest, when all is said in done … Colorectal carcinoma – M1 Non-little cell lung carcinoma – M1 Renal cell carcinoma – M1 Breast malignancy – M1 No proof of adjuvant adequacy so far 2 negative reviews in M0 CRC (C-08, AVANT)

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Adjuvant Antiangiogenic Therapy?

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Bevacizumab Best considered specialist Modest viability in various signs Resistance systems Upregulation of ligand Insoluble VEGF remains and advances angiogenesis? [1] VEGFR-1 polymorphisms (constitutive enactment)? [2] No approved prescient marker Potential high serum VEGF levels? 1. Chen TT, et al. J Cell Biol. 2010;188:595-609. 2. Lambrechts D, et al. ECCO-ESMO 2009. Theoretical 16LBA.

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New Data on Newer Agents Ramucirumab Aflibercept

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Ramucirumab Fully refined counter acting agent coordinated against the VEGFR-2 Potential for insusceptible interceded obliteration of angiogenic vessels Circumvents insoluble VEGF initiation of VEGFR-2 In stage II trials for MBC, propelled GI growths, metastatic GU diseases, intermittent ovarian malignancy, prostate tumor, metastatic RCC In stage III trials for stubborn metastatic gastric adenocarcinoma, progressed NSCLC, backslid hepatocellular carcinoma, metastatic CRC Spratlin and Mackey. Future Oncol. 2010;6:1085-1094.

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TRIO-012 Ramucirumab Study Patient populace Women with HER2-negative, unresectable, locally intermittent or metastatic bosom growth with or without quantifiable sores No past chemotherapy for metastatic or locally repetitive and inoperable bosom malignancy Study arrange Progressive malady Or inadmissible harmfulness Or pulled back assent Docetaxel 75 mg/m² IV q3w RANDOMIZATION … .. 2/3 F/UP Blinded ramucirumab 10 mg/kg IV q3w Docetaxel 75 mg/m² IV q3w … .. 1/3 Blinded fake treatment IV q3w Mackey J, et al. Clin Breast Cancer. 2009;9:258-261.

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Aflibercept Fusion protein imitation receptor: ties VEGF-A, VEGF-B, and placental development consider Achieved essential endpoint (OS) in VELOUR stage III clinical trial for second-line treatment of mCRC 1266 mCRC patients FOLFIRI versus FOLFIRI + aflibercept enhanced OS Regeneron [press release]. Accessible at: Gotten to May 25, 2011.

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Motesanib Small atom inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and KIT Increases action of paclitaxel in MBC in randomized stage II setting, however with noteworthy GI poisonous quality Martin MM, et. al. Lancet Oncol. 2011;12:369-376.

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TRIO-010 Motesanib Study Paclitaxel 90 mg/m² IV week by week for 3/4 wks Roll-over (discretionary) RANDOM I ZAT I ON Arm An Open-name motesanib 125 mg PO day by day PD Blinded fake treatment PO day by day Paclitaxel 90 mg/m² IV week by week for 3/4 wks Arm B Treatment until Progressive ailment Unacceptable harmfulness Consent withdrawal Blinded motesanib 125 mg PO day by day Paclitaxel 90 mg/m² IV week by week for 3/4 wks Arm C Open-name bevacizumab 10 mg/kg on Week 1 and Week 3 N = 282 Stratified by : Previous taxane CT versus different versus none Number of metastatic locales (< 3 versus ≥ 3) Hormone receptor status (positive versus negative) Martin MM, et. al. Lancet Oncol. 2011;12:369-376.

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Vascular Disrupting Agents drugs intended to harm the set up vasculature of tumors bringing about focal putrefaction Flavinoid mixes ASA404 Phase III (NSCLC) microtubule destabilizers CA4P Phase II/III AVE8062 Phase III; sarcoma) ABT-751 Phase II (numerous histologies) Dolastatin Phase II Oxi4503 Phase I Due to leftover edge of practical cells, blend treatment might be required

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Angipoietin - TIE Receptor Pathway TIE-1 and TIE-2 are cell-surface receptors that predicament and are initiated by angiopoietins (ANGPT1, ANGPT2, and ANGPT4) Play critical part in angiogenic switch Agents focusing on ANG1 anad ANGPT2 are in stage II clinical trials and early reports recommend hostile to tumor action and a wellbeing profile unmistakable from against VEGFA operators Substantial mix advantage of focusing on both ANGPT2 and VEGFA pathways preclinically

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Agents Targeting the ANGPT-TIE Pathway

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How Can We Move Beyond Empiricism? Prescient tests

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Therapeutic Predictive Assays Prognostic biomarker "How awful is my disease, Doc?" Predictive biomarker "Is this medication going to work?"

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Exposure Biomarkers Measure biologic reaction after organization of the medication Include: Treatment-developing hypertension Changes in serum VEGF, shed VEGFR-2, PIGF Changes in element differentiate MRI Have been helpful in characterizing pharmacodynamically suitable dosages and calendars Do not deliver regardless of whether to begin antiangiogenic treatment in a given patient Rini B, et al. J Natl Cancer Inst. 2011;103:763-773. Schneider BP. J Clin Oncol. 2008;26:4672-4678. Vlahovic G, et al. J Thoracic Oncol. 2007;8:S745.

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Tumor-Based Predictive Markers Baseline tumor VEGF levels Prognostic yet not prescient Low levels of carbonic anhydrase IX [1] Von Hippel-Lindau loss of capacity changes in M1 renal cell carcinoma [2] HER2 energy in bosom growth Associated with large amounts of VEGF, freely prognostic [3] 1. Hong YS, et. al. BMC Cancer. 2009;9:246 2. Choueri et. al. J Urol 2008. 3. Konecny GE, et. al. Clin Cancer Res. 2004;10:1706-1716

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Blood-Based Biomarkers Baseline circling VEGF levels Variably prognostic, however not prescient [1] Circulating endothelial cell specification May be prognostic in a few malignancies [2,3] Not yet appeared to be prescient 1. Kaseb AO, et al. Malignancy. 2009;115:4895-4906. 2. Batchelor T, et al. ASCO 2007. Theoretical 2001. 3. Ramalingam SS, et al. ASCO 2008. Conceptual 8078.

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Host-Based Predictive Biomarkers Angiogenesis is a reaction of ordinary stroma to signals from the disease Germ-line hereditary fluctuation may add to viability and poisonous quality E2100 MBC paclitaxel ± bevacizumab VEGF-2578AA and VEGF-1154AA genotypes had higher OS in mix [1] Constitutive initiation of VEGFR-1 pathway? [2] 1. Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302. 2. Lambrechts D, et al. ECCO-ESMO 2009. Conceptual 16LBA.

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SNPs Relate to Survival in MBC/Bevacizumab? Little subset, tumor DNA, indistinct what number of SNPs assessed Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302.

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The State of Published Antiangiogenic Trials when all is said in done . . . Unselected diseases Treat whole populace with novel treatment Minimal and additionally review tissue gathering Unplanned review subset investigation

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Ongoing Antiangiogenic Trials . . . Atomic method of reasoning Up-front tumor and physical tissue collection Molecular stratification before treatment (If any indication of prescient marker) Prespecified factual appraisal of biomarker execution

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"It\'s hard to make forecasts, particularly about what\'s to come." Will We Find a Predictive Marker for Antiangiogenic Therapy?

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A Tale of 2 Trials Adjuvant chemotherapy in operable bosom malignancy Standard treatment versus standard treatment + 1 yr of bevacizumab N ~ 3000 patients NCT00625898. NCT00528567.

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Preconditions for a VEGF Pathway Predictive Biomarker Agent restrains this pathway Pretreatment science drives the remedial reaction Compensatory non-VEGF–mediated pathways are unessential Randomized clinical trials with suitable biologic examples Clinical adequacy flag is adequately solid in the touchy subpopulation to drive a measurably noteworthy collaboration test

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Why BETH Should Be a Positive Trial Preselected populace with VEGF-driven science [1] Preclinical (an

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