Cancer gene therapy based on translational control of a...

Details Cancer gene therapy based on translational control of a... Cancer gene therapy based on translational control of a...

2001-07-26

2004-07-06

Nguyen, Dave T. (Department: 1635)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C435S320100, C536S023100, C536S024100

Reexamination Certificate

active

06759394

ABSTRACT:

This invention pertains to a translational control element placed in a vector to cause a selective translation of a toxin, including a toxin that acts by metabolizing a drug to become toxic (a “conditional toxin,” e.g., the herpes simplex virus type-1 thymidine kinase (HTK)/ganciclovir interaction), inside solid tumor cells, while leaving normal cells unaffected due to their inability to translate the toxin encoded by the vector.
The major determinant of morbidity and mortality for patients with a primary malignant tumor is the emergence and progression of metastatic islets resistant to conventional therapy. It has been estimated that at least 50% of patients presenting with a primary tumor already bear metastases at the time of diagnosis. See R. H. Goldfarb et al., “Therapeutic agents for treatment of established metastases and inhibitors of metastatic spread: preclinical and clinical progress,” Current Opinion in Oncology, vol. 4, pp. 1130-41(1992). Cancer gene therapy has developed as a means of attacking cancers resistant to conventional approaches. Much of the work has been directed at targeting characteristics of the primary tumor, with attention to choice of vector and transcriptional regulation. Two examples of this are the use of tissue-specific promoters and inducible promoters. See K. Binley et al., “An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer,” Gene Therapy, vol. 6, pp. 1721-1727 (1999). Despite some advances, these approaches have not successfully addressed the major problem of how to target metastases. Not only are metastases more difficult to reach but, due to their heterogeneity, they frequently do not maintain the specific gene expression pattern of the primary tumor, upon which gene therapy is generally designed. See S. J. Hall et al., “Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer,” Cancer Gene Therapy, vol. 6, pp. 54-63 (1999). There is an unfilled need for an effective in vivo cancer gene therapy that permits selective killing of both the primary tumor and distant metastases, while distinguishing cancer cells from normal cells.
One of the main obstacles to gene therapy has been the difficulty of successfully targeting cancer cells, while not harming normal cells. Indeed, it has been found that even when therapeutic vectors are delivered locally to a primary tumor, systemic effects still often occur, indicating that the vector has become blood-borne. See Z. Long et al., “Molecular evaluation of biopsy and autopsy specimens from patients receiving in vivo retroviral gene therapy, Human Gene Therapy, vol. 10, pp.:733-40 (1999); and M. Kaloss et al., “Distribution of retroviral vectors and vector producer cells using two routes of administration in rats,” Gene Therapy, vol. 6, pp. 1389-1396 (1999). One approach to circumvent this problem is to use elements allowing specific transcriptional regulation of the vector, e.g., the use of tissue-specific promoters and inducible promoters. See Binley et al., 1999; and L. M. Anderson et al., “Adenovirus-mediated tissue-targeted expression of the HSVtk gene for the treatment of breast cancer,” Gene Therapy, vol. 6, pp. 854-864 (1999). While these approaches are very promising, they require specific knowledge of the cancer cells, and are not applicable to most situations.
The use of suicide genes is one of the most promising strategies for gene therapy of solid tumors. Transfection of the herpes simplex virus type-1 thymidine kinase gene (HTK), given in combination with the drug ganciclovir (GCV), is the most commonly used cancer gene therapy system to date, both in experimental models and clinical trials. See J. Gomez-Navarro et al., “Gene therapy for cancer,” European Journal of Cancer, vol. 35, pp. 867-885 (1999). HTK, whose substrate specificity is distinct from that of cellular thymidine kinases, can convert GCV to the toxic phosphorylated form, specifically killing the cells that express HTK. Since the concept of an HTK/GCV system was first described, it has shown good success as a tumor ablation strategy in a variety of experimental models. In addition, over two dozen clinical gene therapy trials based on this model have been initiated in the last seven years. See J. A. Roth et al., “Gene therapy for cancer: what have we done and where are we going?” Journal of the National Cancer Institute, vol. 89(1), pp. 21-39 (1997); D. Klatzmann et al., “A Phase I/II dose-escalation study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent metastatic melanoma,” Human Gene Therapy, vol. 9, pp. 2585-2894 (1998); and J. R. Herman et al.,“In situ gene therapy for adenocarcinoma of the prostate: A phase I clinical trial,” Human Gene Therapy, vol. 10, pp. 1239-1249 (1999).
The HTK/GCV system is appealing due to its low inherent toxicity. Moreover, it has been shown that when as few as 10% of the cancer cells express HTK, it is still possible to obtain complete tumor ablation due to the “bystander effect” and specific immune responses. See R. Ramesh et al., “In vivo analysis of the ‘bystander effect’: a cytokine cascade,” Experimental Hematology, vol. 24, pp. 829-838 (1996).
To direct the expression HTK primarily in cancer cells, most research to date has been based on either specific transcriptional regulation or specific delivery methods. Two examples of the former strategy are the use of tissue-specific promoters and inducible promoters. See Anderson et al., 1999; and Binley et al., 1999.
The protein eIF4E is the cap-binding subunit of the eIF4F complex, an ATP-dependent helicase that unwinds “excess” secondary structure in the 5′ untranslated region (UTR) of mRNAs. The low-abundance of eIF4E/F is the limiting factor for the translation of some mRNAs, particularly those with long, G/C-rich 5′ UTRs with the potential to form a stable, secondary structure. See M. J. Clemens et al., “Translational control: the cancer connection,” Int. J. Biochem. Cell Biol., vol. 31, pp. 1-23 (1999). Overexpression of eIF4E results in a specific increase in the translation of these weakly competitive mRNAs, many of which encode products that stimulate cell growth and angiogenesis, like FGF-2 and VEGF. See C. Kevil et al., “Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation,” Oncogene, vol. 11, pp. 2339-2348 (1995); C. Kevil et al., “Translational regulation of Vascular Permeability Factor by eukaryotic initiation factor 4E: Implications for tumor angiogenesis,” Int. J. Cancer, vol. 65, pp. 785-790 (1996); and P. A. E. Scott et al., “Differential expression of vascular endothelial growth factor mRNA versus protein isoforms expression in human breast cancer and relationship to eIF4E,” British. J. Cancer, vol. 77, pp. 2120-2128 (1998).
Elevating eIF4E rescues the translation of repressed mRNAs with a complex 5′ UTR, many of which encode factors required for cell proliferation, e.g., protooncogene c-myc, cyclin D1, ornithine decarboxylase, fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor (“VEGF,” otherwise known as vascular permeability factor, “VPF”). See A. De Benedetti et al., “eIF4E expression in tumors: its possible role in progression of malignancies,” Int. J. of Biochemistry and Cell Biology, vol. 31, pp. 59-72 (1999).
Overexpression of eIF4E has been shown to be ubiquitous in solid tumors, including bladder, breast, cervical, colon, head and neck, and prostate, as well as in many malignant cell lines. See J. P. Crew et al., Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression,” Br. J. Cancer, vol. 82, pp. 161-166 (2000); V. V. Kerekatte et al., “The protooncogene/translation initiation factor eIF4E: a survey of its expression in breast carcinomas,” Int. J. Cancer., vol. 64, pp. 27-31 (1995);

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