alexa Eradication of Human Ovarian Cancer Cells by Transgenic Expression of Recombinant <i>DNASE1</i>, <i>DNASE1L3</i>, <i>DNASE2</i>, and <i>DFFB</i> Controlled by <i>EGFR</i> Promoter: Novel Strategy for Targeted Therapy of Cancer? | Abstract
ISSN: 2157-7412

Journal of Genetic Syndromes & Gene Therapy
Open Access

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Research Article

Eradication of Human Ovarian Cancer Cells by Transgenic Expression of Recombinant DNASE1, DNASE1L3, DNASE2, and DFFB Controlled by EGFR Promoter: Novel Strategy for Targeted Therapy of Cancer?

Marek Malecki1-3*, Jessica Dahlke3, Melissa Haig3, Lynn Wohlwend3 and Raf Malecki1,4
1PBMEF, San Francisco, CA 94105, USA
2NMRFM, NIH, Madison, WI 53706, USA
3UW, Madison, WI 53706, USA,
4SFSU, San Francisco, CA 94132, USA
Corresponding Author : Marek Malecki MD PhD
Phoenix Biomolecular Engineering Foundation
San Francisco, CA 94105-191111, USA
Tel: 4157134370
E-mail: [email protected]
Received May 03, 2013; Accepted July 17, 2013; Published July 21, 2013
Citation: Malecki M, Dahlke J, Haig M, Wohlwend L, Malecki R (2013) Eradicationof Human Ovarian Cancer Cells by Transgenic Expression of RecombinantDNASE1, DNASE1L3, DNASE2, and DFFB Controlled by EGFR Promoter:Novel Strategy for Targeted Therapy of Cancer. J Genet Syndr Gene Ther 4 (6): 152: 1-10. doi:10.4172/2157-7412.1000152
Copyright: © 2013 Malecki M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Ovarian cancer is the most deadly among all gynecological cancers. Patients undergoing systemic therapies of advanced ovarian cancers suffer from horrendous side effects. Cancer survivors and their offspring suffer from iatrogenic consequences of systemic therapies: genetic mutations. The ultimate goal of our work is development of therapies, which selectively and completely eliminate cancer cells, but do not harm healthy cells. An important consideration for attaining this goal is the fact that ovarian cancer cells over-express EGFR or its mutants, what becomes the factor discriminating them from healthy cells - a potential facilitator of personalized therapy.

Specific aim: The specific aim of this project was threefold: (1) to bioengineer suicide genes’ carrying vectors guided by synthetic antibodies for EGFRvIII and EGFR; (2) to genetically engineer DNA constructs for the human, recombinant DNASE1, DNASE1L3, DNASE2, and DFFB controlled by the EGFR promoter; (3) to selectively eradicate ovarian cancer cells by intranuclear targeting of the transgenically expressed recombinant DNases.

Methods: Synthetic antibodies for EGFR and EGFRvIII were selected from the human library and used to bioengineer biotag-guided transgenes’ vectors. Coding sequences for the human DNASE1, DNASE1L3, DNASE2, DFFB controlled by the EGFR promoter were amplified from the human cDNA and genetically engineered into the plasmid constructs also coding for the fusions with NLS and GFP. The vectors carrying transgenes for the DNases were delivered in vitro into human ovarian cancer cells from ascites and cultures.

Results: Synthetic antibody guided vectors delivered the transgenes for the recombinant DNases efficiently into the ovarian cancer cells. Transgenic expression and nuclear targeting of the DNases in those cells resulted in destruction of their genomes and led to their death, as validated by labeling with the molecular death tags. In healthy cells, which did not over-express EGFR, no changes were recorded.

Conclusion: Targeted expression of the recombinant DNASE1, DNASE1L3, DNASE2, DFFB in the ovarian cancers in vitro resulted in their complete eradication, but had no effects upon the healthy cells. This novel therapeutic strategy has a potential for streamlining it into in vivo trials, as personalized, targeted therapy of ovarian and other cancers.

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