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Investigational New Drugs

, Volume 29, Issue 6, pp 1475–1481 | Cite as

A multicenter, phase II study of Bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma

  • Manish A. ShahEmail author
  • Derek G. Power
  • Hedy L. Kindler
  • Kyle D. Holen
  • Margaret M. Kemeny
  • David H. Ilson
  • Laura Tang
  • Marinela Capanu
  • John J. Wright
  • David P. Kelsen
PHASE II STUDIES

Summary

Purpose The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma. Experimental Design We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m2 was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1. Results We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0–22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB. Conclusions Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.

Keywords

Bortezomib Proteasome Gastric cancer Nuclear factor-kB (NF-KB) 

Notes

Acknowledgements

Supported by the NCI Phase II Contract–NO1-CM17105 (PI David P. Kelsen, MD), and NCI Translational Research Contract 24XS072 NCI 6003 (PI Manish A. Shah, MD)

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Van Cutsem E, Kang K, Chung H et al (2009) Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). American Society of Clinial Oncology, Annual Proceedings, Orlando, FL, USA. May 29th–June 2nd; Abstract #LBA 4509Google Scholar
  3. 3.
    Bang Y, Chung H, Xu J et al (2009) Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial. Amercan Society of Clinical Oncology, Annual Proceedings, Orlando, FL, 29 May–2 June 2009; Abstract #4556Google Scholar
  4. 4.
    Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428PubMedGoogle Scholar
  5. 5.
    Lenz HJ (2003) Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev 29(Suppl 1):41–48PubMedCrossRefGoogle Scholar
  6. 6.
    Cusack JC (2003) Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev 29(Suppl 1):21–31PubMedCrossRefGoogle Scholar
  7. 7.
    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436PubMedCrossRefGoogle Scholar
  8. 8.
    Yamanaka N, Sasaki N, Tasaki A et al (2004) Nuclear factor-kappaB p65 is a prognostic indicator in gastric carcinoma. Anticancer Res 24:1071–1075PubMedGoogle Scholar
  9. 9.
    Sasaki N, Morisaki T, Hashizume K et al (2001) Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7:4136–4142PubMedGoogle Scholar
  10. 10.
    Rajkumar SV, Richardson PG, Hideshima T, Anderson KC (2005) Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23:630–639PubMedCrossRefGoogle Scholar
  11. 11.
    Fujita T, Doihara H, Washio K et al (2007) Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells. Anticancer Drugs 18:677–686PubMedCrossRefGoogle Scholar
  12. 12.
    Bae SH, Ryoo HM, Kim MK et al (2008) Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapeutic agents in gastric cancer cell lines. Oncol Rep 19:1027–1032PubMedGoogle Scholar
  13. 13.
    Stein HJ, Feith M, Siewert JR (2000) Cancer of the esophagogastric junction. Surg Oncol 9:35–41PubMedCrossRefGoogle Scholar
  14. 14.
    Aghajanian C, Soignet S, Dizon DS et al (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505–2511PubMedGoogle Scholar
  15. 15.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  16. 16.
    Mattioli E, Vogiatzi P, Sun A et al (2007) Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer. J Cell Physiol 210:183–191PubMedCrossRefGoogle Scholar
  17. 17.
    Prall F, Ostwald C, Nizze H, Barten M (2004) Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis. Appl Immunohistochem Mol Morphol 12:111–121PubMedGoogle Scholar
  18. 18.
    Lee BL, Lee HS, Jung J et al (2005) Nuclear factor-kappaB activation correlates with better prognosis and Akt activation in human gastric cancer. Clin Cancer Res 11:2518–2525PubMedCrossRefGoogle Scholar
  19. 19.
    Brandt S, Kwok T, Hartig R et al (2005) NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci U S A 102:9300–9305PubMedCrossRefGoogle Scholar
  20. 20.
    Nozaki K, Tanaka H, Ikehara Y et al (2005) Helicobacter pylori-dependent NF-kappa B activation in newly established Mongolian gerbil gastric cancer cell lines. Cancer Sci 96:170–175PubMedCrossRefGoogle Scholar
  21. 21.
    Mackay H, Hedley D, Major P et al (2005) A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res 11:5526–5533PubMedCrossRefGoogle Scholar
  22. 22.
    Kondagunta GV, Drucker B, Schwartz L et al (2004) Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22:3720–3725PubMedCrossRefGoogle Scholar
  23. 23.
    Li T, Ho L, Piperdi B et al (2009) Phase II study of the proteasome inhibitor bortezomib (PS-341, Velcade((R))) in chemotherapy-naive patients with advanced stage non-small cell lung cancer (NSCLC). Lung Cancer 11:11Google Scholar
  24. 24.
    Lara PN Jr, Chansky K, Davies AM et al (2006) Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327). J Thorac Oncol 1:996–1001PubMedCrossRefGoogle Scholar
  25. 25.
    Dees EC, Orlowski RZ (2006) Targeting the ubiquitin-proteasome pathway in breast cancer therapy. Future Oncol 2:121–135PubMedCrossRefGoogle Scholar
  26. 26.
    Shah MH, Young D, Kindler HL et al (2004) Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res 10:6111–6118PubMedCrossRefGoogle Scholar
  27. 27.
    Aghajanian C, Blessing JA, Darcy KM et al (2009) A phase II evaluation of bortezomib in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 115:215–220PubMedCrossRefGoogle Scholar
  28. 28.
    Lee BY, Lee HS, Jung J et al (2005) Nuclear factor-kB activation correlates with better prognosis and Akt activation in human gastric cancer. Clin Cancer Res 11:2518–2525PubMedCrossRefGoogle Scholar
  29. 29.
    Ooi CH, Ivanova T, Wu J et al (2009) Oncogenic pathway combinations predict clinical prognosis in gastric cancer. PLoS Genetics 5:1–13CrossRefGoogle Scholar
  30. 30.
    Chauhan D, Catley L, Li G et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8:407–419PubMedCrossRefGoogle Scholar
  31. 31.
    Cusack JC Jr, Liu R, Xia L et al (2006) NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model. Clin Cancer Res 12:6758–6764PubMedCrossRefGoogle Scholar
  32. 32.
    Sloss CM, Wang F, Liu R et al (2008) Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells. Clin Cancer Res 14:5116–5123PubMedCrossRefGoogle Scholar
  33. 33.
    Chauhan D, Li G, Shringarpure R et al (2003) Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 63:6174–6177PubMedGoogle Scholar
  34. 34.
    Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedCrossRefGoogle Scholar
  35. 35.
    Ling YH, Liebes L, Ng B et al (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 1:841–849PubMedGoogle Scholar
  36. 36.
    Loo TW, Clarke DM (1998) Superfolding of the partially unfolded core-glycosylated intermediate of human P-glycoprotein into the mature enzyme is promoted by substrate-induced transmembrane domain interactions. J Biol Chem 273:14671–14674PubMedCrossRefGoogle Scholar
  37. 37.
    Cusack JC Jr, Liu R, Houston M et al (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61:3535–3540PubMedGoogle Scholar
  38. 38.
    Ocean AJ, Schnoll-Sussman F, Chen XE et al (2007) Recent results of phase II study of PS-341 (bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA). Gastrointestinal Cancer Symposium, Orlando, FL, USA, 15–17 January 2007Google Scholar
  39. 39.
    Jatoi A, Dakhil SR, Foster NR et al (2008) Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esopahgeal, gastric, and gastroesophageal cancer. J Thorac Oncol 3:516–520PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Manish A. Shah
    • 1
    • 2
    Email author
  • Derek G. Power
    • 1
    • 2
  • Hedy L. Kindler
    • 4
  • Kyle D. Holen
    • 5
  • Margaret M. Kemeny
    • 6
  • David H. Ilson
    • 1
    • 2
  • Laura Tang
    • 7
  • Marinela Capanu
    • 3
  • John J. Wright
    • 8
  • David P. Kelsen
    • 1
    • 2
  1. 1.Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of MedicineWeill-Cornell Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of Epidemiology and BiostatisticsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Section of Hematology/OncologyUniversity of Chicago Medical CenterChicagoUSA
  5. 5.Paul P. Carbone Comprehensive Cancer CenterUniversity of WisconsinMadisonUSA
  6. 6.Department of Surgical OncologyQueens Cancer Center at Queens HospitalJamaicaUSA
  7. 7.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  8. 8.Investigational Drug Branch, Cancer Therapy Evaluation ProgramNational Cancer InstituteRockvilleUSA

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