Integrin Targeted Therapy for the Treatment of Ovarian Cancer

DESCRIPTION (provided by applicant): Although prevention and early detection are the ultimate goals, the fact remains that 21,990 women in 2011 will be diagnosed with ovarian cancer in the U.S. Of these women 75% will be confronted with a high stage tumorand a five-year survival rate of 28%, which cannot be ignored. For these patients, improved treatment strategies for residual disease following surgery will aid in the reduction of complications during therapy as well as decrease the risk of cancer recurrence, which in turn would reduce mortality and improve the quality of life significantly. Given that ovarian cancer is predominantly confined to the peritoneal cavity, the strategy of localized intraperitoneal (IP) chemotherapy is highly desirable. Site-specific treatment results in tumor exposure of up to a 1000-fold increase in drug levels compared to what is possible with systemic delivery while reducing systemic toxicity. Especially in patients with minimal tumor burden after surgical debulking, regimens of IP chemotherapy are effective and lead to an increased progression-free and overall survival, but are accompanied with many side effects that are unacceptable to patients. In this study, it is proposed to use animal models of OC to evaluate IP treatment of early stage OC, mimicking disease recurrence, using the novel anti-invasive and anti-angiogenic disintegrin vicrostatin (VCN), a recombinant protein, impregnated in a carboxymethyl cellulose (CMC) and polyethylene oxide (PEO) gel approved for human use in Europe and Australia for prevention of post-surgical adhesions. This approach combines the benefits of high-concentration local peritoneal treatment as well as sustained drug delivery. Additionally, the CMC-PEO gel has the added benefit of preventing/reducing formation of post-surgical adhesions, a significant source of morbidity and therefore an important consideration in the management of ovarian cancer. Research goal: Using mouse models of ovarian cancer, the project will investigate the local andsustained effect of VCN delivered via a CMC-PEO gel on ovarian cancer growth and progression. In the initial studies we will determine the optimal formulation and ratios of CMC-PEO gel and VCN for maximizing the duration and level of VCN release under in vitro conditions. The CMC-PEO gel as a delivery vehicle is unique for several reasons: the viscous gel has the ability to hold VCN in suspension and slowly release it over time. This sustained slow release allows for maximization of the time the residual tumor is exposed to pharmacologic concentrations of the drug. Further, VCN diffusion from CMC-PEO gel provides for a continuous anti-tumor and anti-angiogenic affect. This proposed research has the capacity to make a significant impact in the management of ovarian cancer via treating residual disease and thereby decreasing mortality and increasing survival. Further, this translational research has the capability of impacting the morbidity associated with ovarian cancer by preventing the formation of post-surgical adhesions. PUBLIC HEALTH RELEVANCE: Ovarian cancer (OC) accounts for ~3% of all cancers in women and ranks fifth in cancer deaths of women; it is most often diagnosed at an advanced stage. The American Cancer Society estimates that approximately 21,990 new cases of ovarian cancer (OC) will occur in the United States in 2011 and it will be responsible for 15,460 deaths. The combination of debulking surgery and cytotoxic chemotherapy is the primary treatment modality. The overall 1-, 5-, and 10-year survival of ovarian cancer patients is 75%, 46%, and 38%, respectively. If OC is diagnosed at the localized stage, the 5-year survival rate is 94%; however, only 15% of all cases are detected at this stage. This application will demonstrate that vicrostatin (VCN), a disintegrin targeting integrins involved in OC progression and angiogenesis, is an effective and novel therapy for OC. We propose three Specific Aims: in the first Specific Aim we will evaluate the in vitro the release kinetics of VCN impregnated in Oxiplex for use as a novel delivery modality. In the second aim we will compare Oxiplex-VCN to VCN and a nanosomal form of VCN as an OC therapeutic in an in vivo mouse OC model. In the third we will evaluate the efficacy of VCN released from Oxiplex in a model of OC recurrence following surgical debulking. It is hoped that these proof of concept studies will aid in the development of both a novel therapeutic agent as well as a novel drug delivery system.