Skip to main content

Advertisement

Log in

Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo

Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1–3, 8–10, and 15–17, plus paclitaxel (90 mg/m2) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel–bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Marks PA, Richon VM, Breslow R, Rifkind RA (2001) Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 13(6):477–483

    Article  PubMed  CAS  Google Scholar 

  2. Fuino LBP, Wittman S et al (2003) Histone deacetylse inhibitor LAQ824 down regulated Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone. B Mol Cancer Ther 2:971–984

    CAS  Google Scholar 

  3. Isaacs JS, Xu W, Neckers L (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3(3):213–217

    Article  PubMed  CAS  Google Scholar 

  4. Yang Y, Rao R, Shen J, Tang Y, Fiskus W, Nechtman J, Atadja P, Bhalla K (2008) Role of acetylation and extracellular location of heat shock protein 90 alpha in tumor cell invasion. Cancer Res 68(12):4833–4842

    Article  PubMed  CAS  Google Scholar 

  5. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–458

    Article  PubMed  CAS  Google Scholar 

  6. Marcus AI, Zhou J, O’Brate A, Hamel E, Wong J, Nivens M, El-Naggar A, Yao TP, Khuri FR, Giannakakou P (2005) The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res 65(9):3883–3893

    Article  PubMed  CAS  Google Scholar 

  7. Owonikoko TK, Ramalingam SS, Kanterewicz B, Balius TE, Belani CP, Hershberger PA (2010) Vorinostat increases carboplatin and paclitaxel activity in non-small-cell lung cancer cells. Int J Cancer 126(3):743–755

    Article  PubMed  CAS  Google Scholar 

  8. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM et al (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL) [erratum appears in Blood 2007 Jun 15;109(12):5086] Blood 109(1):31–39

  9. Kelly WK, O’Connor OA, Krug LM et al (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid in patients with advanced cancer. J Clin Oncol 23:3923–3931

    Article  PubMed  CAS  Google Scholar 

  10. Luu TH, Morgan RJ, Leong L et al (2008) A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium Study. Clin Cancer Res 14:7138–7142

    Article  PubMed  CAS  Google Scholar 

  11. Bali P, Pranpat M, Swaby R, Fiskus W, Yamaguchi H, Balasis M, Rocha K, Wang H, Richon V, Bhalla K (2005) Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplificatoin of Her 2. Clin Cancer Res 11(17):6382–6389

    Article  PubMed  CAS  Google Scholar 

  12. Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res 13(16):4882–4890

    Article  PubMed  CAS  Google Scholar 

  13. Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV et al (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21(3):427–436

    Article  PubMed  CAS  Google Scholar 

  14. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676

    Article  PubMed  CAS  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC (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(3):205–216

    Article  PubMed  CAS  Google Scholar 

  16. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10

    Article  PubMed  CAS  Google Scholar 

  17. Miller KD, Wang M, Gralow J et al (2005) E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc Am Soc Clin Oncol, Late breaking session

  18. Ree AH, Dueland S, Folkvord S, Hole KH, Seierstad T, Johansen M, Abrahamsen TW, Flatmark K (2010) Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the pelvic radiation and vorinostat (PRAVO) phase 1 study. Lancet Oncol 11(5):459–464

    Article  PubMed  CAS  Google Scholar 

  19. Galanis E, Jaeckle KA, Maurer MJ et al (2009) Phase II trial of vorinostat in recurrent glioblastoma multiforme: a North Central cancer treatment Group study. J Clin Oncol 27(12):2052–2058

    Article  PubMed  CAS  Google Scholar 

  20. Angelucci A, Mari M, Millimaggi D, Giusti I, Carta G, Bologna M, Dolo V (2010) Suberoylanilide hydroxamic acid partly reverses resistance to paclitaxel in human ovarian cancer cell lines. Gynecol Oncol 119(3):557–563

    Article  PubMed  CAS  Google Scholar 

  21. Burstein HJ (2011) Bevacizumab for advanced breast cancer: all tied up with a RIBBON? J Clin Oncol 29(10):1232–1235

    Article  PubMed  CAS  Google Scholar 

  22. Dickson MA, Rathkopf DE, Carvajal RD et al (2011) A phase I pharmacokinetic study of pulse-dosevorinostat with flavopiridol in solid tumors. Invest New Drugs 29:1004–1012

    Article  PubMed  CAS  Google Scholar 

  23. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas S, Espinoza-Delgado I, Vokes EE, Gandara DR et al (2010) Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 28(1):56–62

    Article  PubMed  CAS  Google Scholar 

  24. NCT00473889: A phase II/III randomized, double-blind study of paclitaxel plus carboplatin in combination with vorinostat or placebo in patients with stage IIIB (with pleural effusion) or stage IV non-small-cell lung cancer (NSCLC). clinicaltrials.gov

  25. Ha K, Fiskus W, Rao R, Balusu R, Venkannagari S, Nalabothula NR, Bhalla KN (2011) Hsp90 inhibitor-mediated disruption of chaperone association of ATR with hsp90 sensitizes cancer cells to DNA damage. Mol Cancer Ther 10(7):1194–1206

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments:

This study was supported by United States Department of Health and Human Service contract N01-CM-62204 (P.I. Joseph A. Sparano, MD) and N01-CM-62207 (PI: Miguel Villalona, MD), and N01 CM62205 (PI: Charles Erlichman MD).

Disclosures

The authors have no relevant disclosures except Dr. Vered Stearns who has received research funding from Merck.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B. Ramaswamy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 42 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramaswamy, B., Fiskus, W., Cohen, B. et al. Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. Breast Cancer Res Treat 132, 1063–1072 (2012). https://doi.org/10.1007/s10549-011-1928-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1928-x

Keywords

Navigation