The majority of solid cancers are of epithelial origin. A hallmark of epithelial cells are tight and adherens junctions. Tight and adherens junctions seal intercellular spaces and significantly limit the perfusion of anti- tumor agents such as drugs, antibodies, and immune cells within the tumor, thus severely diminishing the efficacy of such therapeutic modalities. The epithelial phenotype of cancer cells also represents a barrier to infection with commonly used adenoviruses (Ads) that target CD46 or the coxsackie-adenovirus receptor (CAR), due to trapping of these receptors in tight and adherens junctions which explains, in part, why these serotypes are inefficient in cancer gene therapy. We found however, that specific human species B adenoviruses, namely Ad3, Ad7, Ad11, and Ad14 (AdB-group 2) that use a yet unknown receptor (receptor X), which is different from CAR and CD46, efficiently infect epithelial cancer cells. This makes these serotypes potential tools for virotherapy of cancer as well as for gene transfer into normal epithelial tissue. In addition, these serotypes are important pathogens, exemplified by recent outbreaks of a highly pathogenic new Ad14 stain (Ad14a) that also uses receptor X. Furthermore, we have shown that recombinant Ad3 dodecahedra (PtDd) formed through interaction of 12 penton bases with protruding fibers can enter epithelial cancer cells and faciliate uptake of Ads (and potentially other tumor agents) for which tight and adherens junctions represent a barrier. Based on the importance of Ad3, 7, 11, and 14 as pathogens and potential vectors for gene therapy, the central goals of this proposal are to identify receptor X, to delineate the mechanism of AdB- group 2 and PtDd uptake in normal and malignant epithelial cells, and to develop AdB-group 2 vectors and PtDd-derivatives as vehicles for gene or drug delivery into epithelial cancers.
In cancers of epithelial origin, tight and adherens junctions seal intercellular spaces and severely diminish the efficacy of anti-tumor agents. The central goals of this proposal are to understand how adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 infect normal and malignant epithelial cells and to develop derivatives of these adenoviruses as vehicles for gene or drug delivery into epithelial cancers.
|Beyer, Ines; Cao, Hua; Persson, Jonas et al. (2013) Transient removal of CD46 is safe and increases B-cell depletion by rituximab in CD46 transgenic mice and macaques. Mol Ther 21:291-9|
|van Rensburg, R; Beyer, I; Yao, X-Y et al. (2013) Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells. Gene Ther 20:201-14|
|Beyer, Ines; Cao, Hua; Persson, Jonas et al. (2012) Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. Clin Cancer Res 18:3340-51|
|Wang, Hongjie; Li, Zong-Yi; Liu, Ying et al. (2011) Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nat Med 17:96-104|
|Wang, Hongjie; Li, ZongYi; Yumul, Roma et al. (2011) Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions. J Virol 85:6390-402|
|Beyer, Ines; van Rensburg, Ruan; Strauss, Robert et al. (2011) Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer. Cancer Res 71:7080-90|
|Strauss, Robert; Li, Zong-Yi; Liu, Ying et al. (2011) Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS One 6:e16186|
|Wang, Hongjie; Liu, Ying; Li, Zong-Yi et al. (2010) A recombinant adenovirus type 35 fiber knob protein sensitizes lymphoma cells to rituximab therapy. Blood 115:592-600|