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Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group

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Summary

Purpose To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. Experimental Design This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m2 IV on d1, 4, 8, 11) and doxorubicin (15 mg/m2 IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. Results Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. Conclusions The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.

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References

  1. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC, Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498

    Article  CAS  PubMed  Google Scholar 

  2. Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S, O’Connor OA, Shi H, Boral AL, Fisher RI (2009) Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 20(3):520–525

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Traenckner EB, Wilk S, Baeuerle PA (1994) A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J 13(22):5433–5441

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78(5):773–785

    Article  CAS  PubMed  Google Scholar 

  5. Nagata Y, Anan T, Yoshida T, Mizukami T, Taya Y, Fujiwara T, Kato H, Saya H, Nakao M (1999) The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the hsp90 association. Oncogene 18(44):6037–6049

    Article  CAS  PubMed  Google Scholar 

  6. An WG, Hwang SG, Trepel JB, Blagosklonny MV (2000) Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 14(7):1276–1283

    Article  CAS  PubMed  Google Scholar 

  7. Alessandrini A, Chiaur DS, Pagano M (1997) Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. Leukemia 11(3):342–345

    Article  CAS  PubMed  Google Scholar 

  8. Hui B, Shi YH, Ding ZB, Zhou J, Gu CY, Peng YF, Yang H, Liu WR, Shi GM, Fan J (2012) Proteasome inhibitor interacts synergistically with autophagy inhibitor to suppress proliferation and induce apoptosis in hepatocellular carcinoma. Cancer 118(22):5560–5571

    Article  CAS  PubMed  Google Scholar 

  9. Spratlin JL, Pitts TM, Kulikowski GN, Morelli MP, Tentler JJ, Serkova NJ, Eckhardt SG (2011) Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines. Anticancer Res 31(4):1093–1103

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Baiz D, Pozzato G, Dapas B, Farra R, Scaggiante B, Grassi M, Uxa L, Giansante C, Zennaro C, Guarnieri G, Grassi G (2009) Bortezomib arrests the proliferation of hepatocellular carcinoma cells HepG2 and JHH6 by differentially affecting E2F1, p21 and p27 levels. Biochimie 91(3):373–382

    Article  CAS  PubMed  Google Scholar 

  11. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5):417–421

    Article  CAS  PubMed  Google Scholar 

  12. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61(7):3071–3076

    CAS  PubMed  Google Scholar 

  13. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277(19):16639–16647

    Article  CAS  PubMed  Google Scholar 

  14. Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61(9):3535–3540

    CAS  PubMed  Google Scholar 

  15. Liu P, Kimmoun E, Legrand A, Sauvanet A, Degott C, Lardeux B, Bernuau D (2002) Activation of NF-kappa B, AP-1 and STAT transcription factors is a frequent and early event in human hepatocellular carcinomas. J Hepatol 37(1):63–71

    Article  PubMed  Google Scholar 

  16. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431(7007):461–466

    Article  CAS  PubMed  Google Scholar 

  17. Liu TZ, Hu CC, Chen YH, Stern A, Cheng JT (2000) Differentiation status modulates transcription factor NF-kappaB activity in unstimulated human hepatocellular carcinoma cell lines. Cancer Lett 151(1):49–56

    Article  CAS  PubMed  Google Scholar 

  18. Lee BH, Kim MS, Rhew JH, Park RW, de Crombrugghe B, Kim IS (2000) Transcriptional regulation of fibronectin gene by phorbol myristate acetate in hepatoma cells: a negative role for NF-kappaB. J Cell Biochem 76(3):437–451

    Article  CAS  PubMed  Google Scholar 

  19. Ros JE, Schuetz JD, Geuken M, Streetz K, Moshage H, Kuipers F, Manns MP, Jansen PL, Trautwein C, Muller M (2001) Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling. Hepatology 33(6):1425–1431

    Article  CAS  PubMed  Google Scholar 

  20. Richmond A (2002) Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2(9):664–674

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Raman D, Baugher PJ, Thu YM, Richmond A (2007) Role of chemokines in tumor growth. Cancer Lett 256(2):137–165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Wang D, Dubois RN, Richmond A (2009) The role of chemokines in intestinal inflammation and cancer. Curr Opin Pharmacol 9(6):688–696

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Mayo MW, Wang CY, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ, Baldwin AS Jr (1997) Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278(5344):1812–1815

    Article  CAS  PubMed  Google Scholar 

  24. Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26(3):203–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Sakurai T, Maeda S, Chang L, Karin M (2006) Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103(28):10544–10551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kim GP, Mahoney MR, Szydlo D, Mok TS, Marshke R, Holen K, Picus J, Boyer M, Pitot HC, Rubin J, Philip PA, Nowak A, Wright JJ, Erlichman C (2012) An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. Investig New Drugs 30(1):387–394

    Article  CAS  Google Scholar 

  27. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101(6):2377–2380

    Article  CAS  PubMed  Google Scholar 

  28. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Roussos E, Neeser J, Mikail A, Adams J, Sjak-Shie N, Vescio RA, Berenson JR (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9(3):1136–1144

    CAS  PubMed  Google Scholar 

  29. Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, Hui P, Ma B, Lam KC, Ho WM, Wong HT, Tang A, Johnson PJ (2005) A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97(20):1532–1538

    Article  CAS  PubMed  Google Scholar 

  30. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390

    Article  CAS  PubMed  Google Scholar 

  31. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB (2010) Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304(19):2154–2160

    Article  CAS  PubMed  Google Scholar 

  32. LoConte NK, Thomas JP, Alberti D, Heideman J, Binger K, Marnocha R, Utecht K, Geiger P, Eickhoff J, Wilding G, Kolesar J (2008) A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer. Cancer Chemother Pharmacol 63(1):109–115

    Article  CAS  PubMed  Google Scholar 

  33. Lazennec G, Richmond A (2010) Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med 16(3):133–144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Wood LD, Richmond A (1995) Constitutive and cytokine-induced expression of the melanoma growth stimulatory activity/GRO alpha gene requires both NF-kappa B and novel constitutive factors. J Biol Chem 270(51):30619–30626

    Article  CAS  PubMed  Google Scholar 

  35. Su Y, Amiri KI, Horton LW, Yu Y, Ayers GD, Koehler E, Kelley MC, Puzanov I, Richmond A, Sosman JA (2010) A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res 16(1):348–357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  37. Cox DR (1972) Regression models and life tables. J R Stat Soc B34:187–220

    Google Scholar 

  38. Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50(3):163–170

    CAS  PubMed  Google Scholar 

  39. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T (2006) Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 66(21):10517–10524

    Article  CAS  PubMed  Google Scholar 

  40. Maeda S, Hikiba Y, Sakamoto K, Nakagawa H, Hirata Y, Hayakawa Y, Yanai A, Ogura K, Karin M, Omata M (2009) Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression. Hepatology 50(6):1851–1860

    Article  CAS  PubMed  Google Scholar 

  41. Loeffler S, Fayard B, Weis J, Weissenberger J (2005) Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer 115(2):202–213

    Article  CAS  PubMed  Google Scholar 

  42. Ashizawa T, Okada R, Suzuki Y, Takagi M, Yamazaki T, Sumi T, Aoki T, Ohnuma S, Aoki T (2005) Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor. Gastric Cancer 8(2):124–131

    Article  CAS  PubMed  Google Scholar 

  43. Matzaraki V, Alexandraki KI, Venetsanou K, Piperi C, Myrianthefs P, Malamos N, Giannakakis T, Karatzas S, Diamanti-Kandarakis E, Baltopoulos G (2007) Evaluation of serum procalcitonin and interleukin-6 levels as markers of liver metastasis. Clin Biochem 40(5–6):336–342

    Article  CAS  PubMed  Google Scholar 

  44. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089):1798–1801

    Article  CAS  PubMed  Google Scholar 

  45. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60(19):5334–5339

    CAS  PubMed  Google Scholar 

  46. Moriuchi H, Moriuchi M, Fauci AS (1997) Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. J Immunol 158(7):3483–3491

    CAS  PubMed  Google Scholar 

  47. Nencioni A, Schwarzenberg K, Brauer KM, Schmidt SM, Ballestrero A, Grunebach F, Brossart P (2006) Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood 108(2):551–558

    Article  CAS  PubMed  Google Scholar 

  48. Yang X, Lu P, Fujii C, Nakamoto Y, Gao JL, Kaneko S, Murphy PM, Mukaida N (2006) Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression. Int J Cancer 118(8):1869–1876

    Article  CAS  PubMed  Google Scholar 

  49. Koizumi K, Hojo S, Akashi T, Yasumoto K, Saiki I (2007) Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci 98(11):1652–1658

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis), and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625, an SRCS award from the Department of Veterans Affairs, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Laboratory correlatives were supported by Public Health Service Grant 5R21 CA099269-02 from the National Cancer Institute.

Ethical standards

The experiments described in this manuscript comply with the current laws of the United States of America.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, A445A Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43212, USA

    Kristen K. Ciombor

  2. Dana Farber Cancer Institute, Boston, MA, USA

    Yang Feng

  3. Northwestern University, Chicago, IL, USA

    Al Bowen Benson III & Mary Mulcahy

  4. Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China

    Yingjun Su

  5. Vanderbilt University, Nashville, TN, USA

    Linda Horton, Sarah P. Short, Ann Richmond & Jordan Berlin

  6. Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    Linda Horton & Ann Richmond

  7. Emory University, Atlanta, GA, USA

    John Sae Wook Kauh & Charles Staley

  8. New York, NY, USA

    Mark Powell

  9. Celgene Corporation, Summit, NJ, USA

    Katayoun I. Amiri

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  1. Kristen K. Ciombor
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Correspondence to Kristen K. Ciombor.

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Ciombor, K.K., Feng, Y., Benson, A.B. et al. Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group. Invest New Drugs 32, 1017–1027 (2014). https://doi.org/10.1007/s10637-014-0111-8

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