Our long-term goal is to develop an adenovirus (Ad)-based therapy for invasive cervical carcinoma (ICC). Over the past 5 years, we have generated and tested a series of oncolytic Ad vectors that possess modified capsids for tumor targeting and utilize a new concept to achieve tumor-specific gene expression and replication. In animal models, we have demonstrated that these vectors are non-toxic and eliminate metastases derived from human tumor cell lines after systemic vector application. The goal of this proposal is to further increase the clinical utility of our oncolytic vector. i) Ad transduction, replication, and oncolysis will be studied on a representative number (N>65) of primary invasive cervical cancer (ICC) cultures that we will obtain through collaborations with hospitals in Seattle and Dakar, Senegal. ii) Our vectors will be based on serotype B adenoviruses that have the potential to efficiently and specifically infect malignant tumor cells and that have low serum prevalence in humans. iii) We will employ new principles to achieve tumor-specific viral replication and to express pro-apoptotic gene products from Ad vectors. iv) DNA microarrays will be used to identify cellular pathways/factors the affect Ad replication and oncolysis, to construct a panel of genes that predicts which cancer patients would benefit from therapy with oncolytic vectors, and to arm our oncolytic vector with genes that enhance viral replication and lysis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080192-08
Application #
7228111
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Yovandich, Jason L
Project Start
1999-03-18
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$226,398
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang et al. (2016) Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models. Hum Gene Ther 27:325-37
Saydaminova, Kamola; Strauss, Robert; Xie, Min et al. (2016) Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells. Cancer Biol Ther 17:1079-1088
Richter, Maximilian; Yumul, Roma; Wang, Hongjie et al. (2015) Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin. Mol Ther Methods Clin Dev 2:15005
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Carter, Darrick; Lieber, André (2014) Protein engineering to target complement evasion in cancer. FEBS Lett 588:334-40
Lu, Zhuo-Zhuang; Wang, Hongjie; Zhang, Yiyi et al. (2013) Penton-dodecahedral particles trigger opening of intercellular junctions and facilitate viral spread during adenovirus serotype 3 infection of epithelial cells. PLoS Pathog 9:e1003718
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
Wang, Hongjie; Yumul, Roma; Cao, Hua et al. (2013) Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2. J Virol 87:11346-62
Strauss, Robert; Bartek, Jiri; Lieber, André (2013) Analysis of EMT by flow cytometry and immunohistochemistry. Methods Mol Biol 1049:355-68

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