Adenovirus vectors have been evaluated for their efficacy in treating cancer. As cancer is the second leading cause of death in the U.S. and current therapeutics are not always sufficient, new cancer therapies are desired. Replication-competent oncolytic adenovirus vectors have been designed to kill cancer cells as part of the virus life cycle. Our laboratory has developed a series of unique oncolytic adenovirus vectors based on the overexpression of an adenovirus-coded protein named ADP. ADP promotes virus release from the cell late in infection and aids in the cell-to-cell spread of adenovirus. Our hypothesis is that high level of expression of ADP will increase the ability of the vector to spread from cell-to-cell in the tumor and thereby destroy the tumor. Our vectors are efficacious in destroying human cancer cells in cell culture and suppressing the growth of tumors in immunodeficient (nude) mice. The human xenograft-nude mouse model is commonly used to evaluate oncolytic adenovirus vectors because the dogma holds that human adenoviruses do not replicate in animals. A more realistic animal model that is permissive or at least semi-permissive for human adenovirus replication and that has an intact immune system would be of great value to the field of oncolytic adenovirus cancer gene therapy. We have identified the Syrian hamster as an animal model for oncolytic adenovirus vectors with promising results. We found that adenovirus is able to infect, replicate, and spread from cell-to-cell in cancer cell lines of this animal. Adenovirus replicates in the lungs, liver, and other organs. Our oncolytic adenovirus vector suppresses the growth of three different hamster tumors and replicates within these tumors. The toxicity and pharmacokinetic biodistribution of our vector as well as wild-type adenovirus and replication-defective adenovirus controls have been determined following intravenous administration of these viruses. We propose to further develop this animal model for oncolytic adenovirus cancer gene therapy.
In Specific Aim 1 we will investigate the interaction between the host, vector, and tumor cells. We will examine vector replication and spreading in tumors, identify factors such as tumor architecture, vector resistance, or immunity that limit the efficacy of vectors, and study the role of the immune system in suppressing tumor growth.
In Specific Aim 2 we will determine the effect of radiation and chemotherapy on the efficacy of Ad vectors, both in cell culture and in the animal model.
In Specific Aim 3 we will investigate the efficacy of replication-selective vectors in this model and attempt to develop orthotopic lung metastasis and pancreatic cancer models in the hamster. These studies should help advance our vectors and possibly oncolytic adenovirus vectors from other research groups toward clinical trials. Although not proposed specifically in this application, these studies should also provide novel information on adenovirus pathogenesis. ? ? ?
|Ying, Baoling; Toth, Karoly; Spencer, Jacqueline F et al. (2015) Transcriptome sequencing and development of an expression microarray platform for liver infection in adenovirus type 5-infected Syrian golden hamsters. Virology 485:305-12|
|Dhar, D; Toth, K; Wold, W S M (2014) Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters. Cancer Gene Ther 21:171-8|
|Wold, William S M; Toth, Karoly (2013) Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther 13:421-33|
|Young, B A; Spencer, J F; Ying, B et al. (2013) The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors. Cancer Gene Ther 20:521-30|
|Young, B A; Spencer, J F; Ying, B et al. (2013) The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model. Cancer Gene Ther 20:531-7|
|Dhar, Debanjan; Toth, Karoly; Wold, William S M (2012) Syrian hamster tumor model to study oncolytic Ad5-based vectors. Methods Mol Biol 797:53-63|
|Ying, Baoling; Tollefson, Ann E; Wold, William S M (2010) Identification of a previously unrecognized promoter that drives expression of the UXP transcription unit in the human adenovirus type 5 genome. J Virol 84:11470-8|
|Tarakanova, Vera L; Wold, William S M (2010) Adenovirus E1A and E1B-19K proteins protect human hepatoma cells from transforming growth factor beta1-induced apoptosis. Virus Res 147:67-76|
|Toth, K; Kuppuswamy, M; Shashkova, E V et al. (2010) A fully replication-competent adenovirus vector with enhanced oncolytic properties. Cancer Gene Ther 17:761-70|
|Spencer, J F; Sagartz, J E; Wold, W S M et al. (2009) New pancreatic carcinoma model for studying oncolytic adenoviruses in the permissive Syrian hamster. Cancer Gene Ther 16:912-22|
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