Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Reovirus as an experimental therapeutic for brain and leptomeningeal metastases from breast cancer

Gene Therapy volume 11, pages 1579–1589 (2004)Cite this article

Abstract

Brain and leptomeningeal metastases are common in breast cancer patients and our current treatments are ineffective. Reovirus type 3 is a replication competent, naturally occurring virus that usurps the activated Ras-signaling pathway (or an element thereof) of tumor cells and lyses them but leaves normal cells relatively unaffected. In this study we evaluated reovirus as an experimental therapeutic in models of central nervous system (CNS) metastasis from breast cancer. We found all breast cancer cell lines tested were susceptible to reovirus, with >50% of these cells lysed within 72 h of infection. In vivo neurotoxicity studies showed only mild local inflammation at the injection site and mild communicating hydrocephalus with neither diffuse encephalitis nor behavioral abnormalities at the therapeutically effective dose of reovirus (intracranial) (ie 107 plaque-forming units) or one dose level higher. In vivo, a single intratumoral administration of reovirus significantly reduced the size of tumors established from two human breast cancer cell lines and significantly prolonged survival. Intrathecal administration of reovirus also remarkably prolonged survival in an immunocompetent racine model of leptomeningeal metastases. These data suggest that the evaluation of reovirus as an experimental therapeutic for CNS metastases from breast cancer is warranted.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Posner JB, Chernik NL . Intracranial metastases from systemic cancer. Adv Neurol 1978; 19: 579–592.

    CAS  PubMed  Google Scholar 

  2. Tsukata Y, Fouad A, Pickren JW, Lane WW . Central nervous system metastasis from breast carcinoma: autopsy study. Cancer 1983; 52: 2349–2354.

    Article  Google Scholar 

  3. Lee YTN . Patterns of metastasis and natural courses of breast carcinoma. Cancer Metast Rev 1985; 4: 153–172.

    Article  CAS  Google Scholar 

  4. Lee YTN . Breast carcinoma: pattern of recurrence and metastasis after mastestomy. Am J Clin Oncol 1984; 7: 334–344.

    Google Scholar 

  5. Boogerd W, VOs VW, Hart AAM, Baris G . Brain metastases in breast cancer: natural history, prognostic factors and outcome. J Neuro-Oncol 1993; 15: 165–174.

    Article  CAS  Google Scholar 

  6. Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.

    Article  CAS  PubMed  Google Scholar 

  7. Makower D et al. Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res 2003; 9: 693–702.

    PubMed  Google Scholar 

  8. Habib N et al. Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma. Cancer Gene Ther 2002; 9: 254–259.

    Article  CAS  PubMed  Google Scholar 

  9. Markert JM et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Therapy 2000; 7: 867–874.

    Article  CAS  PubMed  Google Scholar 

  10. Pecora AL et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 2002; 20: 2251–2266.

    Article  CAS  PubMed  Google Scholar 

  11. Toda M, Rabkin SD, Martuza RL . Treatment of human breast cancer in a brain metastatic model by G207, a replication-competent multimutated herpes simplex virus 1. Hum Gene Ther 1998; 9: 2177–2185.

    Article  CAS  PubMed  Google Scholar 

  12. Randazzo BP et al. Treatment of experimental murine melanoma with a neuroattenuated herpes simplex virus 1 mutant. Virology 1995; 211: 94–101.

    Article  CAS  PubMed  Google Scholar 

  13. Tyler K, Fields BN . Reoviruses. In: Fields BN, Knipe DM, Howley PM, Chanock RM, Melnick JL, Monath TP (eds). Virology, 3nd edn Lippincott-Raven: Philadelphia, PA, 1996, pp 1597–1623.

    Google Scholar 

  14. Sherry B et al. Lymphocytes protect against and are not required for reovirus-induced myocarditis. J Virol 1993; 67: 6119–6124.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Raine CS, Fields BN . Reovirus type III encephalitis – a virologic and ultrastructural study. J Neropathol Exp Neurol 1973; 32: 19–33.

    Article  CAS  Google Scholar 

  16. Paul RW, Choi AHC, Lee PWK . The alpha-anomeric form of sialic acid is the minimal receptor determinant recognized by reovirus. Virology 1989; 172: 382–385.

    Article  CAS  PubMed  Google Scholar 

  17. Choi AHC, Paul RW, Lee PWK . Reovirus binds to multiple plasma membrane proteins on mouse L fibroblasts. Virology 1990; 178: 316–320.

    Article  CAS  PubMed  Google Scholar 

  18. Barton ES et al. Junction adhesion molecule is a receptor for reovirus. Cell 2001; 104: 441–451.

    Article  CAS  PubMed  Google Scholar 

  19. Coffey MC et al. Reovirus therapy of tumors with activated ras pathway. Science 1998; 282: 1332–1334.

    Article  CAS  PubMed  Google Scholar 

  20. Strong JE, Tang D, Lee PW . Evidence that the epidermal growth factor receptor on host cells confers reovirus infection efficiency. Virology 1993; 197: 405–411.

    Article  CAS  PubMed  Google Scholar 

  21. Strong JE, Lee PW . The v-erbB oncogene confers enhanced cellular susceptibility to reovirus infection. J Virol 1996; 70: 612–616.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Strong J et al. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J 1998; 17: 3351–3362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Norman KL et al. Reovirus oncolysis of human breast cancer. Hum Gene Ther 2002; 13: 641–652.

    Article  CAS  PubMed  Google Scholar 

  24. Wilcox ME et al. Reovirus as an oncolytic agent against experimental human malignant gliomas. J Natl Cancer Inst 2001; 93: 903–912.

    Article  CAS  PubMed  Google Scholar 

  25. Yang WQ et al. Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma. Cancer Res 2003; 63: 3162–3172.

    CAS  PubMed  Google Scholar 

  26. Hirasawa K et al. Oncolytic reovirus against ovarian and colon cancer. Cancer Res 2002; 62: 1696–1701.

    CAS  PubMed  Google Scholar 

  27. Hirasawa K et al. Systemic reovirus therapy of metastatic cancer in immune-competent mice. Cancer Res 2003; 63: 348–353.

    CAS  PubMed  Google Scholar 

  28. Alain T et al. Reovirus therapy of lymphoid malignancies. Blood 2002; 100: 4146–4153.

    Article  CAS  PubMed  Google Scholar 

  29. Thirukkumaran CM et al. Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation. Blood 2003; 102: 377–387.

    Article  CAS  PubMed  Google Scholar 

  30. Etoh T et al. Oncolytic viral therapy for human pancreatic cancer cells by reovirus. Clin Cancer Res 2003; 9: 1218–2123.

    CAS  PubMed  Google Scholar 

  31. Slamon DJ et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  32. Ross JS, Fletcher JA . The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 1998; 3: 237–252.

    CAS  PubMed  Google Scholar 

  33. Ben-levy R, Paterson HF, Marshall CJ, Yarden YA . A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J 1994; 13: 3302–3311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Koenders PG et al. Epidermal growth factor receptor-negative tumors are predominantly confined to the subgroup of estradiol receptor-positive human primary breast cancers. Cancer Res 1991; 51: 4544–4548.

    CAS  PubMed  Google Scholar 

  35. Verbeek BS et al. c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 1996; 180: 383–388.

    Article  CAS  PubMed  Google Scholar 

  36. Walter EZ et al. Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. Exp Neurol 1992; 116: 122–132.

    Article  Google Scholar 

  37. Thifault S et al. Comparisons between C57BL/6J and A/J mice in motor activity and coordination, hole-poking, and spatial learning. Brain Res Bull 2001; 58: 213–218.

    Article  Google Scholar 

  38. Sutherland RJ, Richard HD . Place navigation by rats in a swimming pool. Canad J Psychol 1984; 38: 322–347.

    Article  Google Scholar 

  39. Morris RGM, Garrud P, Rawlins JNP, O'Keefe J . Place navigation impaired in rats with heppocampal lesions. Nature 1982; 297: 681–683.

    Article  CAS  PubMed  Google Scholar 

  40. Sagar SM, Price KJ . An experimental model of leptomeningeal metastases employing rat mammary carcinoma cells. J Neurooncol 1995; 23: 15–21.

    Article  CAS  PubMed  Google Scholar 

  41. Yang M et al. Whole-body optical imaging of green flourescent protein-expressing tumors and metastases. Proc Natl Acad Sci USA 2000; 97: 1206–1211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jacobs C, Rubsamen H . Expression of pp60c-src protein kinase in adult and fetal human tissue: High activities in some sarcomas and mammary carcinomas. Cancer Res 1983; 43: 1696–1702.

    CAS  PubMed  Google Scholar 

  43. Shackney SE et al. Intracellular coexpression of epidermal growth factor receptor, Her-2/neu, and p21ras in human breast cancers: evidence for the existence of distinctive patterns of genetic evolution that are common to tumors from different patients. Clin Cancer Res 1998; 4: 913–928.

    CAS  PubMed  Google Scholar 

  44. Carter P et al. Humanization of an antip185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992; 89: 4285–4289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Clynes RA, Towers TL, Presta LG, Ravetch JV . Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000; 6: 443–446.

    Article  CAS  PubMed  Google Scholar 

  46. Ikeda K et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral response. Nat Med 1999; 5: 881–887.

    Article  CAS  PubMed  Google Scholar 

  47. Clarke P et al. Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection. Oncogene 2001; 20: 6910–6919.

    Article  CAS  PubMed  Google Scholar 

  48. Connolly JL et al. Reovirus-induced apoptosis requires activation of transcription factor NF-kappaB. J Virol 2000; 74: 2981–2989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Clarke P et al. Reovirus-induced apoptosis is mediated by TRAIL. J Virol 2000; 74: 8135–8139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clarke P et al. Reovirus infection activates JNK and the JNK-dependent transcription factor c-Jun. J Virol 2001; 75: 11275–11283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Richardson-Burns SM, Kominsky DJ, Tyler KL . Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated with the activation of death receptors. J Neurovirol 2002; 8: 365–380.

    Article  CAS  PubMed  Google Scholar 

  52. Kominsky DJ, Bickel RJ, Tyler KL . Reovirus-induced apoptosis requires both death receptor- and mitochondrial-mediated caspase-dependent pathways of cell death. Cell Death Differ 2002; 9: 926–933.

    Article  CAS  PubMed  Google Scholar 

  53. Morris D et al. A phase I clinical trial evaluating intralesional Reolysin (reovirus) in histologically confirmed malignancies. Proc Am Soc Clin Oncol 2002; 21:92:24a.

Download references

Acknowledgements

This work was funded by the National Cancer Institute of Canada (NCIC) with funds raised from the Canadian Cancer Society, the Canadian Institutes of Health Research (CIHR), the Alberta Cancer Board and the Kid's Cancer Care Foundation (KCCF). WQY is a KCCF fellow and DS is an Alberta Heritage for Medical Research fellow. KN is supported by an AHFMR studentship. We thank the families of Dr Micheal Longinotto, Gordon Stewart, Grant Tims and Clark Smith for their support.

Author information

Authors and Affiliations

  1. Departments of Oncology and Clinical Neurosciences, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada

    WQ Yang, DL Senger, XQ Lun, H Muzik, ZQ Shi, D Stewart & PA Forsyth

  2. Department of Psychology, University of Calgary, Calgary, Alberta, Canada

    RH Dyck

  3. Departments of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada

    K Norman

  4. Department of Epidemiology, Prevention and Screening, Tom Baker Cancer Centre, Calgary, Alberta, Canada

    PMA Brasher

  5. Department of Pathology, University of Calgary, Calgary, Alberta, Canada

    NB Rewcastle & D George

  6. Departments of Microbiology and Infectious Diseases, Dalhousie University, Halifax, Canada

    PWK Lee

Authors
  1. WQ Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. DL Senger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. XQ Lun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Muzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. ZQ Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. RH Dyck
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Norman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. PMA Brasher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. NB Rewcastle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D George
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. PWK Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. PA Forsyth
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, W., Senger, D., Lun, X. et al. Reovirus as an experimental therapeutic for brain and leptomeningeal metastases from breast cancer. Gene Ther 11, 1579–1589 (2004). https://doi.org/10.1038/sj.gt.3302319

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302319

Keywords

This article is cited by

Search

Advanced search

Quick links