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 Potential Conflict of Interest • Dr. Robert S. Kerbel – Consultant (2004-present) • • • • • • • Adnexus SAB member GSK MolMed Oxigene Taiho Pharmaceuticals Japan YM Biosciences Bioessays 13: 31-36, 1991 Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents Kerbel RS 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 ? 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 breast prostate failure or small PFS benefit only when bevacizumab combined with chemotherapy; no OS benefit colon breast ovarian gastric prostate and failure of 1st adjuvant phase III trials ‘CO8’ in CRC ‘AVANT’ in CRC Llovet JM et al., N Engl J Med 359: 378-390, 2008 Sorafenib in advanced hepatocellular carcinoma Yu et al (RS Kerbel) Science 295: 1526-1528, 2002 Effect of p53 status on tumor response to antiangiogenic therapy Conclusions: 1.Antiangiogenic therapy selectively enriches for p53 mutant cells resistance 2. p53 mutant cells reside in more hypoxic regions distal to blood vessels Some Proposed Modes of Acquired Resistance to VEGF Pathway–Targeting Antiangiogenic Drugs Selection of variants having enhanced ability to survive under hypoxic conditions “Evasive resistance” Target one pathway (eg, VEGF) and a compensatory, alternate pathway takes over (eg, bFGF, IL-8, ……) Rapid vascular remodeling (maturation) of remaining tumor vasculature, or “vascular co-option” VEGF is a dominant player in tumor angiogenesis – but there are lots of other backups, eg, PlGF Dll4 (VEGFR-1) (notch receptors) IL-8 (Tie2) Sex hormones (CXCR4 receptor) bFGF (FGFRs) Angiopoietins SDF-1 PDGF HGF/SF (c-met receptor) 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. A B C D initiate anti-bFGF(R) therapy initiate and maintain anti-VEGF(R2) therapy VEGF tumor ` mass VEGF bFGF robust angiogenesis resumes hypoxia VEGF VEGF 'response' E bFGF ‘relapse’ 'response' From: Kerbel RS "Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed" Cancer Cell 8: 269-271, 2005. 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 D Huang et al, Cancer Res 70: 1063-1071, 2010 Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Hypoxia/HIF-1–Mediated Upregulation of Multiple Proangiogenic Growth Factors bFGF antiangiogenic therapy tumor response; elevated hypoxia H1F-1 HGF SDF-1 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 Implications for ‘Sequential / Salvage’ Therapy with VEGF Pathway Inhibitors to Treat Progressive Disease sunitinib response relapse sorafenib sorafenib response relapse sunitinib bevacizumab response relapse sunitinib 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 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 650 Tx Tx 600 550 VEGF [pg/mL] 500 450 400 350 0 7.5 mg/kg 15 mg/kg 30 mg/kg 60 mg/kg 120 mg/kg 300 250 200 150 100 50 0 0 1 R/O 2 3 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 R/O R/O R/O Days C/P Sunitinib treatment of normal mice also increases circulating G-CSF, SDF-1, SCF and OPN in a dosedependent fashion Ebos et al PNAS 104: 17069-74, 2007 VEGF sTIE-2 SDF-1 OPN SCF EPO sVEGFR-2 IL-6 G-CSF PDGF-AB Circulating Bone Marrow-Derived Pro-angiogenic Cell Populations RS Kerbel "Tumor Angiogenesis" New Engl J Med 358: 2039-2049, 2008 Possible consequences of the host-dependent multi-cytokine ‘surge’ induced by antiangiogenic TKIs 1. contribute to tumor flare up/rebound? 2. contribute to drug resistance? 3. contribute to tumor growth/malignant progression? 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 Cancer Cell: Vol 15(3):220-239 March 3, 2009 Protocol for initial examination of the possibility of antiangiogenic drug-induced acceleration of metastatic disease e.g. daily treatment of normal mice with sunitinib for 7 days 1 day e.g. daily treatment of normal mice with vehicle control for 7 days 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 Impact of Sunitinib Pretreatment (or Post-treatment) on Progression of Micrometastases i.v tumor implantation (LM2-4LUC+ Cells) Vehi cl e Group A 120 m g/kg Group B 120 m g/kg Group C 120 m g/kg Group A 3 4 5 6 Group D 60 m g/kg Group E Group B 7 1 2 3 4 5 6 Group C 7 1 2 3 4 5 6 Group D 7 1 2 3 4 5 10 8 7 Tumor Burden [Photons/sec] Days Post Tumor Implantation 1 2 60 m g/kg 14 10 7 21 10 6 27 -7 30 0 7 14 21 Days Post-Implantation Ebos et al. Cancer Cell, 15: 232-239, 2009 28 35 42 Group E 1 2 3 4 5 Impact on Survival Times i.v tumor implantation (LM2-4LUC+ Cells) Vehi cl e Group A 120 m g/kg Group B 120 m g/kg Group C 120 m g/kg 60 m g/kg Group D 60 m g/kg Group E 110 100 90 80 10 7 10 6 Survival (%) Tumor Burden [Photons/sec] 10 8 70 60 50 40 30 20 -7 10 0 Group Group Group Group 7 Group A B C D 14 21 E Days Post-Implantation ** 0 0 5 30 40 28 ** 50 Days Post-Implantation 35 42 * 60 Impact of Long Term Sunitinib Treatment on Established Primary Tumor Growth Mammary f at pad orthotopic tumor implantation (LM2-4LUC+ Cells) Vehi cl e Group A 60 m g/kg Group B 120 m g/kg Group C 2000 Tumor Volume (mm3) 1750 1500 1250 1000 750 500 } 250 **,*** 0 0 7 14 21 28 35 42 Days Post-Implantation Ebos et al., Cancer Cell 15: 232-239, 2009 49 56 63 Short-term adjuvant sunitinib treatment increases spontaneous metastasis after removal of primary human breast cancer xenograft Mammary f at pad orthotopic tumor implantation (LM2-4LUC+ Cells) Primary tumor resection T um ors grown unti l 400 m m 3 Vehi cl e Group A 120 m g/kg Group B 10 9 Group B Group A 10 8 5 Tumor Burden [Photons/sec] Days After Tumor Resection Before 10 7 10 6 30 10 5 0 7 14 21 28 35 42 49 Days Post-Resection (survival times also decreased) Ebos et al., Cancer Cell 15: 232-239, 2009 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……” Phase III Adjuvant Bevacizumab+Chemo NASBP ‘CO8’ Trial in Stage II & III CRC 100 FOLFOX FOLFOX +BEV 1.00 60 80 BEV only 0.80 0.81 0.87 0.74 40 0.60 0.40 0.85 0.6 HR 20 0.20 0.00 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.5 1.0 1.5 2.0 2.5 3.0 DFS (years) “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. 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 Non-tumor SKOV-3-6 SKOV-3-11 SKOV-3-13 K. Hashimoto et al, Mol Cancer Ther 9: 996-1006, 2010 Impact of chronic daily metronomic oral topotecan chemotherapy plus pazopanib days after start of treatment K. Hashimoto et al. Acknowledgments John Ebos Christina Lee Georg Bjarnason Kae Hashimoto Jamie Christensen (Pfizer)