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Robert S. Kerbel, PhD Canada Research Chair in Tumor Biology,

2 nd Quebec Conference on Therapeutic Resistance in Cancer Montreal, November 5, 2010. Acquired (“Evasive”) Resistance to Antiangiogenic Drugs and Tumor Flare-Up. Robert S. Kerbel, PhD Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy

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Robert S. Kerbel, PhD Canada Research Chair in Tumor Biology,

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  1. 2nd Quebec Conference on Therapeutic Resistance in Cancer Montreal, November 5, 2010 Acquired (“Evasive”) Resistance to Antiangiogenic Drugs and Tumor Flare-Up Robert S. Kerbel, PhD Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy Sunnybrook Health Sciences Centre University of Toronto

  2. Potential Conflict of Interest • Dr. Robert S. Kerbel • Consultant (2004-present) • Adnexus • SAB member • GSK • MolMed • Oxigene • Taiho Pharmaceuticals Japan • YM Biosciences

  3. Bioessays 13: 31-36, 1991 Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents Kerbel RS

  4. Nature 390: 404-407, 1997 Antiangiogenic therapy of experimental cancer Does not induce acquired drug resistance Boehm T, Folkman J, Browder T, O'Reilly MS Nature 390: 335-336, 1997 A cancer therapy resistant to resistance Kerbel RS ?

  5. Recent Clinical Trial Results Raising Concerns About Antiangiogenic Therapy 1. Many phase III trials with disappointing results failure of oral TKIs alone or when combined with chemotherapy failure or small PFS benefit only when bevacizumab combined with chemotherapy; no OS benefit colon prostate breast prostate gastric breast ovarian and failure of 1st adjuvant phase III trials ‘CO8’ in CRC ‘AVANT’ in CRC

  6. Llovet JM et al., N Engl J Med 359: 378-390, 2008 Sorafenib in advanced hepatocellular carcinoma

  7. Yu et al (RS Kerbel) Science 295: 1526-1528, 2002 Effect of p53 status on tumor response to antiangiogenic therapy • Conclusions: • Antiangiogenic therapy selectively enriches for p53 mutant cells  resistance • 2. p53 mutant cells reside in more hypoxic regions distal to blood vessels

  8. Some Proposed Modes of Acquired Resistance to VEGF Pathway–Targeting Antiangiogenic Drugs Selection of variants having enhanced ability to survive under hypoxic conditions Rapid vascular remodeling (maturation) of remaining tumor vasculature, or “vascular co-option” “Evasive resistance” Target one pathway (eg, VEGF) and a compensatory, alternate pathway takes over (eg, bFGF, IL-8, ……)

  9. VEGF is a dominant player in tumor angiogenesis – but there are lots of other backups, eg, PlGF (VEGFR-1) SDF-1 (CXCR4 receptor) Dll4 (notch receptors) IL-8 bFGF (FGFRs) PDGF Angiopoietins (Tie2) Sex hormones HGF/SF (c-met receptor)

  10. D A C E B VEGF initiate anti-bFGF(R) therapy initiate and maintain anti-VEGF(R2) therapy VEGF bFGF ` robust angiogenesis resumes hypoxia tumor mass bFGF VEGF VEGF 'response' ‘relapse’ 'response' From: Kerbel RS "Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed" Cancer Cell 8: 269-271, 2005. Cancer Cell 8: 299-309, 2005 Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors Casanovas O, Hicklin DJ, Bergers G, Hanahan D.

  11. Poster presented at the EORTC-NCI-AACR Molecular Targets meeting in Boston, 2009 “Anti-angiogenic therapy using brivanib….in a mouse model of pancreatic neuroendocrine cancer (PNET), results in sustained vascular blockade, without evidence for evasive/acquired resistance …” Elizabeth Allen, Ian B. Walters, I. Celeste Rivera, and Douglas Hanahan • Tumors acquiring resistance to DC101 (a VEGFR-2 Mab) • respond to VEGFR-2/bFGFR antagonist (brivanib) • Also, rapid development of resistance previously detected • using DC101 not observed with brivanib TKI • Efficacy of the drug (brivanib) appears even more effective • when used in the first-line treatment setting

  12. D Huang et al, Cancer Res 70: 1063-1071, 2010 Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.

  13. Hypoxia/HIF-1–Mediated Upregulation of Multiple Proangiogenic Growth Factors bFGF  tumor response; elevated hypoxia antiangiogenic therapy HGF  H1F-1  SDF-1 

  14. Response to Sorafenib, and Subsequent Relapse of Human HCC Tumors Transplanted Into the Liver sorafenibib sorafenibib Therapy initiated ~2 wks after transplantation Days Tang TC, et al (RS Kerbel). Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia , in press, Nov. 2010

  15. Implications for ‘Sequential / Salvage’ Therapy with VEGF Pathway Inhibitors to Treat Progressive Disease sunitinib sorafenib response response relapse relapse sorafenib sunitinib bevacizumab response relapse sunitinib

  16. HJ Burstein et al. (KD Miller), J Clin Oncol 26: 1810-1816, 2008 Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane

  17. Ebos et al., "Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy." Proc Nat'l Acad Sci, USA 104:17069-74, 2007

  18. VEGF sTIE-2 Sunitinib treatment of normal mice also increases circulating G-CSF, SDF-1, SCF and OPN in a dose- dependent fashion SDF-1 OPN SCF EPO sVEGFR-2 IL-6 Ebos et al PNAS 104: 17069-74, 2007 PDGF-AB G-CSF

  19. Circulating Bone Marrow-Derived Pro-angiogenic Cell Populations RS Kerbel "Tumor Angiogenesis" New Engl J Med 358: 2039-2049, 2008

  20. Possible consequences of the host-dependent multi-cytokine ‘surge’ induced by antiangiogenic TKIs • contribute to tumor flare up/rebound? • contribute to drug resistance? • contribute to tumor growth/malignant • progression?

  21. Tumor Flare-up or 'Rebound' After Cessation of Antiangiogenic TKI Therapy Acta Oncol. 48: 927-31, 2009 The reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases. Desar IM, Mulder SF, Stillebroer AB, van Spronsen DJ, van der Graaf WT, Mulders PF, van Herpen CM Acta Oncol. 48: 621-624, 2009 Flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors. Wolter P, Beuselinck B, Pans S, Schoffski P

  22. Cancer Cell: Vol 15(3):220-239 March 3, 2009

  23. 1 day 1 day inject luciferase tagged human breast cancer cells inject luciferase tagged human breast cancer cells evaluate metastatic burden and survival days 5 –30 evaluate metastatic burden and survival days 5 –30 Protocol for initial examination of the possibility of anti- angiogenic drug-induced acceleration of metastatic disease e.g. daily treatment of normal mice with vehicle control for 7 days e.g. daily treatment of normal mice with sunitinib for 7 days

  24. Group A Group B Group C Group D Group E 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 1 2 3 4 5 7 14 21 Days Post Tumor Implantation 27 30 Impact of Sunitinib Pretreatment (or Post-treatment) on Progression of Micrometastases Ebos et al. Cancer Cell, 15: 232-239, 2009

  25. Impact on Survival Times

  26. Impact of Long Term Sunitinib Treatment on Established Primary Tumor Growth Ebos et al., Cancer Cell 15: 232-239, 2009

  27. Group B Group A Before Photons/sec 5 Days After Tumor Resection 30 Short-term adjuvant sunitinib treatment increases spontaneous metastasis after removal of primary human breast cancer xenograft (survival times also decreased) Ebos et al., Cancer Cell 15: 232-239, 2009

  28. Ebos JM et al., Cancer Cell 15: 232-239, 2009 Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. “Our results may be pertinent to the consideration of several prominent issues in cancer therapeutics including…… use of antiangiogenic drugs in the adjuvant setting……”

  29. Phase III Adjuvant Bevacizumab+ChemoNASBP ‘CO8’ Trial in Stage II & III CRC 100 FOLFOX 80 FOLFOX BEV only +BEV 60 40 HR 20 0 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 DFS (years)

  30. “While we originally hoped the significant survival benefit of Avastin seen in metastatic disease in colorectal cancer would be translated to the early setting, it is becoming increasingly clear that the effects of Avastin are different in the metastatic and early disease settings for patients with colon cancer.’’ said Hal Barron, M.D., Head of Global Product Development and Chief Medical Officer at Roche.

  31. SKOV-3-13 Non-tumor SKOV-3-11 SKOV-3-6 Impact of Pazopanib and Metronomic Topotecan Chemotherapy in a Model of Advanced Ovarian Cancer 10 days after intraperitoneal transplantation of luciferase positive SKOV-3 cells SKOV-3-13 K. Hashimoto et al, Mol Cancer Ther 9: 996-1006, 2010

  32. Impact of chronic daily metronomic oral topotecan chemotherapy plus pazopanib % survival days after start of treatment K. Hashimoto et al.

  33. Acknowledgments John Ebos Christina Lee Georg BjarnasonKae Hashimoto Jamie Christensen (Pfizer)

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