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Trials and Tribulations in Developing Clinical Trials of Gene Therapy

E1A for Breast or Ovarian Cancer

  • Chapter
Book cover Gene Therapy for Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

At The University of Texas M.D. Anderson Cancer Center, we have been investigating use of the adenovirus type 5 ElA gene as a cancer therapy for breast or ovarian cancer since 1995. ElA gene therapy is a nonimmunologic approach involving ectopic expression of a potentially therapeutic gene in cancer cells. During the late 1980s, E1A was shown to downregulate the overexpression of HER-2/neu, thus reversing the tumorigenic and metastatic phenotype of HER-2/neu-overexpressing breast and ovarian cancer cells. Since that time, E1A has also been shown to function as a tumor suppressor gene in several other types of tumor cells by inducing apoptosis and differentiation and by inhibiting metastasis regardless of HER2 expression level. This chapter highlights some of the issues and difficulties we encountered in designing clinical trials of E1A gene therapy for breast or ovarian cancer.

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References

  1. Berk AJ. Functions of adenovirus ElA. Cancer Surv 1986;5(2) 367–387.

    PubMed  CAS  Google Scholar 

  2. Ruley HE. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 1983;304(5927) 602–606.

    Article  PubMed  CAS  Google Scholar 

  3. Byrd PJ, Grand RJ, Gallimore PH. Differential transformation of primary human embryo retinal cells by adenovirus El regions and combinations of E1A + Ras. Oncogene 1988;2(5) 477–484.

    PubMed  CAS  Google Scholar 

  4. Montell C, Courtois G, Eng C, Berk A. Complete transformation by adenovirus 2 requires both El A proteins. Cell 1984;36(4) 951–961.

    Article  PubMed  CAS  Google Scholar 

  5. Schrier PI, Bernards R, Vaessen RT, Houweling A, van der Eb AJ. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. Nature 1983;305(5937) 771–775.

    Article  PubMed  CAS  Google Scholar 

  6. Yu D, Suen TC, Yan DH, Chang LS, Hung MC. Transcriptional repression of the neu protooncogene by the adenovirus 5 E1A gene products. Proc Natl Acad Sci U S A 1990;87(12) 4499–4503.

    Article  PubMed  CAS  Google Scholar 

  7. Yan DH, Chang LS, Hung MC. Repressed expression of the HER-2/c-erbB-2 proto-oncogene by the adenovirus Ela gene products. Oncogene 1991;6(2) 343–345.

    PubMed  CAS  Google Scholar 

  8. Yu D, Wolf JK, Scanlon M, Price JE, Hung MC. Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res 1993;53(4) 891–898.

    PubMed  CAS  Google Scholar 

  9. Mymryk JS. Tumour suppressive properties of the adenovirus 5 ElA oncogene. Oncogene 1996; 13(8) 1581–1589.

    PubMed  CAS  Google Scholar 

  10. Frisch SM, Mymryk JS. Adenovirus-5 E1A paradox and paradigm. Nat Rev Mol Cell Biol 2002;3(6) 441–452.

    Article  PubMed  CAS  Google Scholar 

  11. Frisch SM, Reich R, Collier IE, Genrich LT, Martin G, Goldberg GI. Adenovirus ElA represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 1990;5(l) 75–83.

    PubMed  CAS  Google Scholar 

  12. Yu D, Hamada J, Zhang H, Nicolson GL, Hung MC. Mechanisms of c-erbB2/neu oncogene-induced metastasis and repression of metastatic properties by adenovirus 5 E1A gene products. Oncogene 1992;7(11) 2263–2270.

    PubMed  CAS  Google Scholar 

  13. Young KS, Weigel R, Hiebert S, Nevins JR. Adenovirus ElA-mediated negative control of genes activated during F9 differentiation. Mol Cell Biol 1989;9(7) 3109–3113.

    PubMed  CAS  Google Scholar 

  14. van Dam H, Offringa R, Smits AM, Bos JL, Jones NC, van dEA. The repression of the growth factor-inducible genes JE, c-myc and stromelysin by adenovirus E1A is mediated by conserved region 1. Oncogene 1989;4(10) 1207–1212.

    PubMed  Google Scholar 

  15. Pozzatti R, McCormick M, Thompson MA, Khoury G. The E1A gene of adenovirus type 2 reduces the metastatic potential of ras-transformed rat embryo cells. Mol Cell Biol 1988;8 2984–2988.

    PubMed  CAS  Google Scholar 

  16. Rosengard AM, Krutzsch HC, Shearn A, et al. Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development. Nature 1989;342(6246) 177–180.

    Article  PubMed  CAS  Google Scholar 

  17. Frisch SM. Antioncogenic effect of adenovirus E1A in human tumor cells. Proc Natl Acad Sci U S A 1991;88(20) 9077–9081.

    Article  PubMed  CAS  Google Scholar 

  18. Frisch SM, Dolter KE. Adenovirus ElA-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. Cancer Research 1995;55(23) 5551–5555.

    PubMed  CAS  Google Scholar 

  19. Deng J, Xia W, Hung MC. Adenovirus 5 E1A-mediated tumor suppression associated with E1A-mediated apoptosis in vivo. Oncogene 1998;17(17) 2167–2175.

    Article  PubMed  CAS  Google Scholar 

  20. Frisch SM. E1A induces the expression of epithelial characteristics. J Cell Biol 1994;127(4) 1085–1096.

    Article  PubMed  CAS  Google Scholar 

  21. Lowe SW, Ruley HE. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev 1993;7(4) 535–545.

    Article  PubMed  CAS  Google Scholar 

  22. Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 1993;7(4) 546–554.

    Article  PubMed  CAS  Google Scholar 

  23. Lee WP, Wen Y, Varnum B, Hung MC. Akt is required for Axl-Gas6 signaling to protect cells from ElA-mediated apoptosis. Oncogene 2002;21(3) 329–336.

    Article  PubMed  CAS  Google Scholar 

  24. Deng J, Zhang H, Kloosterboer F, et al. Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis. Oncogene 2002;21(l) 44–52.

    Article  PubMed  CAS  Google Scholar 

  25. Lee WP, Liao Y, Robinson D, Kung HJ, Liu ET, Hung MC. Axl-Gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity. Mol Cell Biol 1999; 19(12) 8075–8082.

    PubMed  CAS  Google Scholar 

  26. Chen MJ, Holskin B, Strickler J, et al. Induction by E1A oncogene expression of cellular susceptibility to lysis by TNF. Nature 1987;330(6148) 581–583.

    Article  PubMed  CAS  Google Scholar 

  27. Shao R, Hu MC, Zhou BP, et al. E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IkappaB kinases and nuclear factor kappaB activities. J Biol Chem 1999;274(31) 21,495–21,498.

    Article  CAS  Google Scholar 

  28. Duerksen HP, Wold WS, Gooding LR. Adenovirus E1A renders infected cells sensitive to cytolysis by tumor necrosis factor. J Immunol 1989;143(12) 4193–41200.

    Google Scholar 

  29. Cook JL, May DL, Wilson BA, et al. Role of tumor necrosis factor-alpha in E1A oncogene-induced susceptibility of neoplastic cells to lysis by natural killer cells and activated macrophages. J Immunol 1989;142(12) 4527–4534.

    PubMed  CAS  Google Scholar 

  30. Friedmann T. Overcoming the obstacles to gene therapy. Sci Am 1997;276(6) 96–101.

    PubMed  CAS  Google Scholar 

  31. Zhang Y, Yu D, Xia W, Hung MC. HER-2/neu-targeting cancer therapy via adenovirus-mediated E1A delivery in an animal model. Oncogene 1995;10(10) 1947–1954.

    PubMed  CAS  Google Scholar 

  32. Feigner PL. Nonviral strategies for gene therapy. Sci Am 1997;276(6) 102–106.

    Article  Google Scholar 

  33. Feigner PL, Ringold GM. Cationic liposome-mediated transfection. Nature 1989;337(6205) 387–388.

    Article  Google Scholar 

  34. Nabel EG, Yang Z, Muller D, et al. Safety and toxicity of catheter gene delivery to the pulmonary vasculature in a patient with metastatic melanoma. Hum Gene Ther 1994;5(9) 1089–1094.

    Article  PubMed  CAS  Google Scholar 

  35. Nabel GJ, Nabel EG, Yang ZY, et al. Direct gene transfer with DNA-liposome complexes in melanoma expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA 1993;90(23) 11,307–11,311.

    Article  CAS  Google Scholar 

  36. Xing X, Liu V, Xia W, et al. Safety studies of the intraperitO’Neal injection of E1A—liposome complex in mice. Gene Ther 1997;4(3) 238–243.

    Article  PubMed  CAS  Google Scholar 

  37. Xing X, Zhang S, Chang JY, et al. Safety study and characterization of ElA-liposome complex gene delivery in an ovarian cancer model. Gene Ther 1998;5 1538–1544.

    Article  PubMed  CAS  Google Scholar 

  38. Yu D, Matin A, Xia W, Sorgi F, Huang L, Hung MC. Liposome-mediated in vivo El A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. Oncogene 1995;11(7) 1383–1388.

    PubMed  CAS  Google Scholar 

  39. Chang JY, Xia W, Shao R, et al. The tumor suppression activity of E1A in HER-2/neu-overexpressing breast cancer. Oncogene 1997;14(5) 561–568.

    Article  PubMed  CAS  Google Scholar 

  40. Hortobagyi GN, Hung MC, Lopez-Berestein G. A Phase I multicenter study of E1A gene therapy for patients with metastatic breast cancer and epithelial ovarian cancer that overexpresses HER-2/neu or epithelial ovarian cancer. Hum Gene Ther 1998;9(12) 1775–1798.

    PubMed  CAS  Google Scholar 

  41. Mymryk JS. Tumor suppressive properties of the adenovirus 5 E1A oncogene. Oncogene 1996; 13(8) 1581–1589.

    PubMed  CAS  Google Scholar 

  42. Ueno NT, Yu D, Hung MC. Chemosensitization of HER-2/neu-overexpressing human breast cancer cells to paclitaxel (Taxol) by adenovirus type 5 E1A. Oncogene 1997;15 953–960.

    Article  PubMed  CAS  Google Scholar 

  43. Li S, Huang L. In vivo gene transfer via intravenous administration of cationic lipid-protamine-DNA (LPD) complexes. Gene Ther 1997;4(9) 891–900.

    Article  PubMed  CAS  Google Scholar 

  44. Li S, Rizzo MA, Bhattacharya S, Huang L. Characterization of cationic lipid-protamine-DNA (LPD) complexes for intravenous gene delivery. Gene Ther 1998;5(7) 930–937.

    Article  PubMed  CAS  Google Scholar 

  45. Li S, Wu SP, Whitmore M, et al. Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am J Physiol 1999;276(5 Pt l) L796–L804.

    PubMed  CAS  Google Scholar 

  46. Ueno NT, Bartholomeusz C, Herrmann JL, et al. ElA-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer SKOV3.ipl through apoptosis involving the caspase-3 pathway. Clin Cancer Res 2000;6(l) 250–259.

    PubMed  CAS  Google Scholar 

  47. Ueno NT, Bartholomeusz C, Xia W, et al. Systemic gene therapy in human xenograft tumor models by liposomal delivery of the E1A gene. Cancer Res 2002;62(22) 6712–6716.

    PubMed  CAS  Google Scholar 

  48. Sanchez-Prieto R, Quintanilla M, Cano A, et al. Carcinoma cell lines become sensitive to DNA-damaging agents by the expression of the adenovirus El A gene. Oncogene 1996; 13(5) 1083–1092.

    PubMed  Google Scholar 

  49. Sanchez-Prieto R, Lleonart M, Ramon Y, Cajal SR. Lack of correlation between p53 protein level and sensitivity of DNA-damaging agents in keratinocytes carrying adenovirus Ela mutants. Oncogene 1995;11(4) 675–682.

    PubMed  CAS  Google Scholar 

  50. Sanchez-Prieto R, Vargas JA, Carnero A, et al. Modulation of cellular chemoresistance in keratinocytes by activation of different oncogenes. Int J Cancer 1995;60(2) 235–243.

    Article  PubMed  CAS  Google Scholar 

  51. Zhou Z, Jia SF, Hung MC, Kleinerman ES. E1A sensitizes HER2/neu-overexpressing Ewing’s sarcoma cells to topoisomerase II-targeting anticancer drugs. Cancer Research 2001;61(8) 3394–3398.

    PubMed  CAS  Google Scholar 

  52. Lee WP, Tai DI, Tsai SL, et al. Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine. Cancer Res 2003;63(19) 6229–6236.

    PubMed  CAS  Google Scholar 

  53. Liao Y, Zou YY, Xia WY, Hung MC. Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer. Cancer Gene Ther 2004;11(9) 564–602.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX

    Naoto T. Ueno MD, PhD

  2. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

    Judith K. Wolf MD & Gabriel N. Hortobagyi MD

  3. Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

    David M. Gershenson MD

  4. Department of Molecular & Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

    Mien-Chie Hung PhD

Authors
  1. Naoto T. Ueno MD, PhD
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  2. Judith K. Wolf MD
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  3. David M. Gershenson MD
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  4. Gabriel N. Hortobagyi MD
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  5. Mien-Chie Hung PhD
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Editor information

Editors and Affiliations

  1. The University of Texas M. D. Anderson Cancer Center, Houston, TX

    Kelly K. Hunt MD  & Stephen G. Swisher MD  & 

  2. Inselspital Bern, University of Bern, Bern, Switzerland

    Stephan A. Vorburger MD, MCR

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© 2007 Humana Press Inc., Totowa, NJ

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Ueno, N.T., Wolf, J.K., Gershenson, D.M., Hortobagyi, G.N., Hung, MC. (2007). Trials and Tribulations in Developing Clinical Trials of Gene Therapy. In: Hunt, K.K., Vorburger, S.A., Swisher, S.G. (eds) Gene Therapy for Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-222-9_21

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  • DOI: https://doi.org/10.1007/978-1-59745-222-9_21

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-472-2

  • Online ISBN: 978-1-59745-222-9

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