All ETDs from UAB

Advisory Committee Chair

Selvarangan Ponnazhagan

Advisory Committee Members

Ronald D Alvarez

David M Bedwell

Robin G Lorenz

Gene P Siegal

Theresa V Strong

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Ovarian cancer remains the most lethal gynecological malignancy in the U.S. Conventional therapies have limited therapeutic value due to advanced stage of the disease at diagnosis. Conditionally-replicating adenoviruses (CRAds) are promising, novel anti-cancer agents that are designed to selectively replicate in and lyse tumor cells. In clinical trials, CRAds exhibited limited efficacy thus far. Second generation CRAds are being developed to express a therapeutic protein to further enhance antitumor efficacy. One attractive target in ovarian tumor microenvironment is the matrix metalloproteinases (MMPs) that degrade the extracellular matrix. Thus, tissue inhibitor of metalloproteinase 2 (TIMP2), an endogenous inhibitor of MMPs, is a promising candidate to arm a CRAd intended to treat ovarian cancer. We hypothesize that a CRAD armed with TIMP2 will inhibit ovarian cancer progression through two distinct mechanisms. First, specific replication in tumor cells should lead to oncolysis. Second, secretion of TIMP2 into the tumor microenvironment should inhibit excess extracellular MMPs and activate other MMP-independent signaling pathways to inhibit tumor growth, angiogenesis and metastasis. A targeted and armed CRAd, Ad5/3-CXCR4-TIMP2 was developed using the CXCR4 promoter for enhanced replication, expressing the TIMP2 transgene. First, we confirmed the secretion and functional activity of TIMP2, as demonstrated by the inhibi-tion of gelatin degradation by MMPs. In addition, arming with TIMP2 did not inhibit viral replication nor oncolytic potency, as the TIMP2 armed viruses showed enhanced killing of cancer cells when compared to the unarmed viruses. Examination of viral replication in primary stage III and IV ovarian cancer samples revealed a consistent high level of viral replication with Ad5/3-CXCR4-TIMP2. The therapeutic efficacy of the TIMP2-armed CRAd was then evaluated in an orthotropic model of ovarian cancer, in which athymic mice were intraperitoneally injected with human ovarian cancer cells. The results demonstrated that the Ad5/3-CXCR4-TIMP2 delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This effect was mediated through inhibition of MMPs. Collectively, the present study demonstrated the enhanced therapeutic efficacy of the dual-action, TIMP2-armed CRAd in vivo and the translational potential of using Ad5/3-CXCR4-TIMP2 for treatment in patients with advanced ovarian cancer.

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