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Why did the antibodies fail in adjuvant treatment?

Why did the antibodies fail in adjuvant treatment?. Heinz-Josef Lenz Associate Director, Clinical Research Kathryn Balakrishnan Chair for Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery Co-Leader GI Oncology Program USC/Norris Comprehensive Cancer Center.

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Why did the antibodies fail in adjuvant treatment?

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  1. Why did the antibodies fail in adjuvant treatment? Heinz-Josef Lenz Associate Director, Clinical Research Kathryn Balakrishnan Chair for Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery Co-Leader GI Oncology Program USC/Norris Comprehensive Cancer Center

  2. Why Treatment Failures in Adjuvant Therapy • Tumor Biology (Genetic Make Up) • What do we know? • Host Response (Host Genome/ Microenvironment) • What do we know?

  3. Tumor Biology (PETACC)Multivariate Analysis in whole population Treatment, Sex, Site, KRAS, BRAF,TS, 18qLOH (Stage II: HR 1.4, p=0.33), hTERT: not significant * p values from the Wald test in a multiivariate Cox regression § HR = hazard ratio Tejpar ASCO 2010

  4. Bertagnolli, M. M. et al. J Clin Oncol; 27:1814-1821 2009

  5. Influence of MSI: Prognostic relevance in mutant BRAF

  6. Tumor Biology: Gene Expression Signature in QUASAR 1.0 0.8 0.6 Proportion Event Free 0.4 Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years Recurrence Risk Group 0.2 Low 12% ( 9% -16%) Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046) Intermediate 18% (13%-24%) 22% (16%-29%) High 0.0 0 1 2 3 4 5 Years Kerr et al ASCO 2010

  7. Why an active therapy in advanced disease is not active in the adjuvant setting? • Cytotoxic agents such as Irinotecan failed • Monocloncal Antibodies targeting EGFR and VEGF failed • Is this TRUE in Other Cancers? Or is this Colon Cancer Specific?

  8. Disease-free Survival: Stage II and Stage III Patients 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] p-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 12 18 24 30 36 42 48 54 60 66 72 0 6 Months p=0.258 3.8% p=0.005 7.5% Data cut-off: June 2006

  9. Benefits of Adjuvant Tamoxifen (5 yrs, ER+) Hazard Ratio 0.59 (SE 0.03) Hazard Ratio 0.66 (SE 0.04) EBCTG Lancet 2005

  10. Summary of Trastuzumab AdjuvantTrial DFS Benefits 0 2 1 In favor of T In favor of Obs.

  11. Interactions between Tumor and Normal Cells • Interactions between tumor cells and normal cells result in alterations in several important tumor cell characteristics other than proliferation • Response to Growth Factors are differentially expressed in different organs determining homing of cancer cells • Growth conditions may significantly affect chemosensitivity of tumor cells and metastases in different organs differ in their response to therapy Fidler, 1986;Liotta, 1986; Cavanaugh and Nicolson, 1991a; Fodstad et al., 1988b; Hoffmann, 19921.

  12. Toggle Switch Dormancy to Macroscopic Tumor Klauber-DeMore, N. et al. Biological behavior of human breast cancer micrometastases. Clin. Cancer Res. 7 (2001), pp. 2434-2439. Folkman, J. et al. Cancer: looking outside the genome. Nat. Rev. Mol. Cell Biol. 1 (2000), pp. 76-79. Hanahan, D. and Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell 86 (1996), pp. 353-364. • Below a critical point of cancer cell density and endothelial cell density, cancer will not be able to keep its concentration of angiogenic factors high enough leading to destruction of capillaries • Factor of 17 was reported between MVD between microscopic and macroscopic disease • Switch from dormant to macroscopic disease through balance of pro and anti angiogenic factors.

  13. Experimental models have shown that Dormancy can protect tumor cells from chemotherapy (Naumov et al. Breast Cancer Research and Treatment 82: 199–206, 2003)

  14. Aguirre-Ghisos et al 2007

  15. Dormancy Pathways • Stem Cells • Angiogenesis • Mitosis/Apoptosis • Immunological

  16. Van de Wetering et al. 2002 The Wnt pathway is critical for maintaining homeostasis of the intestinal crypt Barker et al. 2009 Van de Wetering et al. 2002

  17. Stem Cell Markers (LRG5, ALDH, CD44)

  18. Estimated Probability of Survival Years since Diagnosis of Resectable Gastric Cancer Combined analysis of risk alleles of CD44 for overall survival Adjusted P value = 0.019 CD44 1–2 Favorable alleles (n=55) CD44 0 Favorable alleles (n=67) OS: 3.6 yrs OS: 7.3 yrs Winder et al Annals of Oncology 2011

  19. Cytoplasm b-catenin A Critical Cellular Switch Nucleus b-catenin TCF Teo et al., PNAS 2005 Differentiation Non-differentiation CBP p300 ICG-001 b-catenin b-catenin ICG-001 CBP p300 cyclin D1 axin 2 Hnkd Survivin S100A4 b-catenin b-catenin c-jun fra-1 TCF TCF

  20. Colon Cancer Stem Cell Models Miyabayashi T, et al PNAS 104, 5668, 2007

  21. Efficacy of CBP/β-catenin Antagonist on Drug-Resistant Relapsed Primary Colon Tumorgraft normal IgG normal IgG B 3 2 A* C 1 CBP(A22) IP β-catenin Western Blot p300(N15) IP Oxl./PBS Oxl./C88

  22. Day 47 Mice VDL +/- ICG-001 VDL +ICG-001 sacrificed day 115 VDL only sacrificed day 52

  23. Targeted Agents why did they fail? • EGFR • VEGF

  24. FTS binding protein FAP Snail FSP-1 Slug N-cadherin SIP1 Vimentina-SMA Fibronectin Twist b-cateninGoosecoid Ob-cadherin LEF-1 Syndecan-1 FOXC2 miR10b miR21 EGFR Syndecan E-cadherin MUC1 Cytokeratin Desmoplakin ZO-1 a1 (IV) collagen Laminin-1 miR200 family Entactin Is Target expressed in EMT? Adapted from Kalluri & Weinberg, J Clin Invest 119: 1420-8, 2009

  25. EGFR Established Metastasis Primary Tumor Metastasis High High Low EGFR expression during Metastatic Process “EMT status may be a broadly applicable indicator of sensitivity to EGFR inhibitors.” (Barr et al, Clin Exp Metastasis (2008) 25:685–693)

  26. EGFR and VEGF gene expression in adjacent normal tissue predict Recurrence Schneider et al 2004, Pharmacogenomics

  27. VEGF mRNA associated with tumor recurrence in stage II and III colon cancer

  28. VEGF and Il-8 associated recurrence in Stage III disease (n=121)

  29. Integrin SNPs associated with recurrence in stage III disease)

  30. Conclusions • Cytotoxic Therapies miminal or no benefit in adjuvant therapy in colon cancer • Anti-VEGF/EGFR therapies no benefit in adjuvant • Differences in Tumor Biology/Host interaction responsible for difference in chemosensitivity • Toggle Switch: Dormancy in Immunotherapy, Angiogenesis and Growth Factors (Stem Cells)

  31. Future Directions • To induce and/or maintain dormancy of tumor cells • To induce cell death in residual dormant cells by targeting their survival and drug resistance mechanisms • To induce differentiation of cancer stem cells • To identify cellular/serum biomarkers of dormant cancer

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