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Tissue-Specific Promoters Active in CD44⁺CD24^–/low Breast Cancer Cells

¹ Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, ² HUSLAB, ³ Department of Pathology, Helsinki University Central Hospital, ⁴ Genome Scale Biology Program, Biomedicum Helsinki, ⁵ Medical Imaging Center, ⁶ Department of Oncology, and ⁷ Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland; and ⁸ Department of Obstetrics and Gynecology, Duesseldorf University Medical Center, Duesseldorf, Germany

Requests for reprints: Akseli Hemminki, Biomedicum, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland. Phone: 358-9-1912-5464; Fax: 11-358-9-1912-5155; E-mail: akseli.hemminki{at}helsinki.fi.

Key Words: cancer stem cell • oncolytic adenovirus • tissue-specific promoter

It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44⁺CD24^–/low population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44⁺CD24^–/low cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44⁺CD24^–/low cells. -Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44⁺CD24^–/low cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44⁺CD24^–/low cells in vitro. In vivo, these viruses had significant antitumor activity in CD44⁺CD24^–/low–derived tumors. These findings may have relevance for elimination of cancer stem cells in humans. [Cancer Res 2008;68(14):5533–9]