Despite significant improvements in the management of breast cancer, the 5-year survival rate for advanced disease remains dismal, and a majority of women will eventually relapse and die from their disease. It is imperative, therefore, that new treatment modalities be developed for this devastating disease. This Phase I STTR application proposes studies that will facilitate the clinical translation of a novel antiangiogenic agent with potent antitumor activity against breast cancer. To address a major obstacle to the clinical translation of this technology, the reliance on snake venom to produce the protein, we have recently produced a recombinant form of the protein, which we call vicrostatin (VN); VN is as active as the native venom protein, contortrostatin (CN), in vitro and in vivo.
Our aims will focus on the optimization of production of VN and preparation of a liposomal encapsulated form of VN (LVN) suitable for large scale production and clinical application. We will demonstrate efficacy of LVN alone or in combination with chemotherapy in a human mammary cancer mouse model. The mammary carcinoma cells will be stably-transfected with luciferase and we will use the Xenogen small animal imaging system to monitor tumor burden and metastatic spread during therapy. Additionally, we will carry out preliminary toxicological analysis in a rodent model to demonstrate safety of LVN. We hypothesize that: (i) VN can be made at acceptable production levels in a bacterial cell line suitable for cGMP production; (ii) LVN can be prepared by a homogenization method appropriate for mass production; (iii) LVN so produced will have biological efficacy identical to native CN (LCN) following intravenous (IV) delivery in a human breast cancer model, and (iv) LVN will have toxicologic properties suitable for clinical translation. We have established the following Specific Aims and milestones for successful completion of this application:
Specific Aim #1 - Prepare VN in sufficient quantity for clinical application (Milestone 1, months 0-6), and prepare a liposomal formulation of VN (LVN) with appropriate stability characteristics and in amounts suitable for clinical application (Milestone 2, months 0-12).
Specific Aim #2 - Demonstrate biological efficacy of LVN alone and in combination with a currently used chemotherapeutic agent in a mouse model of human breast cancer (Milestone 3, months 9-12).
Specific Aim #3 - Examine toxicologic properties of LVN in rodents using single dose and dose escalation studies (Milestone 4, months 6-12). In Phase II of this STTR we will continue preclinical studies, which will include further examining toxicologic properties to determine safety of LVN, characterizing its pharmacokinetic and organ distribution profile, and further examining animal survival and efficacy of LVN alone and in combination with chemotherapeutic agents. ? ? ?
| Minea, Radu; Helchowski, Corey; Rubino, Barbara et al. (2012) Development of a chimeric recombinant disintegrin as a cost-effective anti-cancer agent with promising translational potential. Toxicon 59:472-86 |
| Minea, Radu O; Helchowski, Corey M; Zidovetzki, Samuel J et al. (2010) Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities. PLoS One 5:e10929 |
