Breast cancer most commonly metastasizes to the skeleton and improvements in therapy for osteolytic bone metastases are required. Oncdlytic adenoviruses tailored to replicate selectively with tumor cells are novel anticancer agents with great therapeutic potential but have shown limited efficacy in the clinical setting. We have demonstrated that efficient oncolysis by a replicating adenovirus is critically dependent on tumor expression of primary adenovirus receptors. A number of studies that have shown that primary cancer cells express low levels of the coxsackievirus and adenovirus receptor, CAR,and are poorly infected by adenoviruses. Moreover, the widespread distribution of CAR on noncancerous tissues presents an obstacle to the selective delivery of replicating adenoviruses to disseminated breast cancer cells upon systemic administration. These two concerns imply that modification of a replication-selective adenovirus to allow efficient and selective CAR-independent infection of target cancer cells could both improve the efficacy of the virus and reduce toxicity to normal cells. In addition, the efficacy of a replication-selective adenovirus could be enhanced by engineering it to deliver a therapeutic transgene. We propose to arm the replicating adenovirus with a secreted therapeutic protein, with a distinct mechanism of action within the local bone microenvironment - osteoprotegerin (OPG), which inhibits bone resorption. We hypothesize that a replication-selective adenovirus armed with OPG would eradicate bone metastases of breast cancer both directly, by oncolysis, and indirectly, by inhibiting osteoclastic bone resorption and thus reducing the tumor burden. Taken together, we propose to combine two distinct strategies to improve the efficacy of replicating adenoviruses for the treatment of bone metastases of breast cancer. The first specific aim is to construct a tropism-modified, armed replicating adenovirus expressing OPG. The second specific aim is to evaluate the efficacy of the tropism-modified, armed replicating adenovirus in vitro. The third specific aim is to evaluate the efficacy of the tropism-modified, armed replicating adenovirus in vivo. This will establish the therapeutic potential of this novel agent for the treatment of bone metastases of breast cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108585-04
Application #
7541414
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Muszynski, Karen
Project Start
2006-03-08
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$225,695
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Cody, James J; Rivera, Angel A; Lyons, Gray R et al. (2013) Expression of osteoprotegerin from a replicating adenovirus inhibits the progression of prostate cancer bone metastases in a murine model. Lab Invest 93:268-78
Yang, Sherry W; Cody, James J; Rivera, Angel A et al. (2011) Conditionally replicating adenovirus expressing TIMP2 for ovarian cancer therapy. Clin Cancer Res 17:538-49
Yang, Sherry W; Chanda, Diptiman; Cody, James J et al. (2011) Conditionally replicating adenovirus expressing TIMP2 increases survival in a mouse model of disseminated ovarian cancer. PLoS One 6:e25131
Wei, Shi; Li, Yufeng; Siegal, Gene P et al. (2011) Breast carcinomas with isolated bone metastases have different hormone receptor expression profiles than those with metastases to other sites or multiple organs. Ann Diagn Pathol 15:79-83
Douglas, Joanne T; Rivera, Angel A; Lyons, Gray R et al. (2010) Ex vivo transfer of the Hoxc-8-interacting domain of Smad1 by a tropism-modified adenoviral vector results in efficient bone formation in a rabbit model of spinal fusion. J Spinal Disord Tech 23:63-73
Cody, J J; Rivera, A A; Lyons, G R et al. (2010) Arming a replicating adenovirus with osteoprotegerin reduces the tumor burden in a murine model of osteolytic bone metastases of breast cancer. Cancer Gene Ther 17:893-905
Kashentseva, Elena A; Douglas, Joanne T; Zinn, Kurt R et al. (2009) Targeting of adenovirus serotype 5 pseudotyped with short fiber from serotype 41 to c-erbB2-positive cells using bispecific single-chain diabody. J Mol Biol 388:443-61
Kimball, Kristopher J; Rivera, Angel A; Zinn, Kurt R et al. (2009) Novel infectivity-enhanced oncolytic adenovirus with a capsid-incorporated dual-imaging moiety for monitoring virotherapy in ovarian cancer. Mol Imaging 8:264-77
Chanda, Diptiman; Isayeva, Tatyana; Kumar, Sanjay et al. (2009) Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in prostate cancer bone metastasis. Clin Cancer Res 15:7175-85
Matthews, Kellie; Noker, Patricia E; Tian, Baohong et al. (2009) Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer. Clin Cancer Res 15:4131-7

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