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Abstract
Grant Number: 1R41CA126001-01A1 Project Title: Development of a combination therapy for the treatment of prostate cancer
PI Information: Name Title MARKLAND, FRANCIS S. markland@usc.edu PROFESSOR AND ACTING CHAIRMAN Abstract: DESCRIPTION (provided by applicant): Prostate cancer (PC) is the second most common form of cancer in American males, second only to skin cancer. In addition, it trails only lung cancer as a cause of death from cancer. The American Cancer Society estimated that 234,460 new cases of PC would be diagnosed in the United States and 27,350 men would die from PC in 2006. Most deaths from prostate cancer are still caused by spread of the cancer cells to remote tissue or organs, most frequently to the skeleton, which are resistant to conventional therapies. It is imperative, therefore, that new treatment modalities be developed for this devastating disease. This Phase I application proposes studies that will aid in the development of and clinical translation of a novel therapeutic regimen which combines conventional chemotherapeutics with the antiangiogenic agent, vicrostatin (VN), which possesses potent antitumor activity against prostate cancer. Our recent studies have shown that we can produce a recombinant version of CN (since the recombinant protein contains features found both in CN as well as other disintegrins, the recombinant protein we produce has been given the name vicrostatin, VN, a combination of viper and croatalid disintegrin sequences) that is as active as the native protein both in vitro and in vivo. In this Phase I proposal we will demonstrate that a liposomal formulation of VN (LVN) can be prepared in a form suitable for clinical use. Further, we will show that intravenous (IV) delivery of this formulation in a mouse model of prostate cancer produces effective control of tumor growth, angiogenesis and metastasis. We hypothesize that: (i) VN can be produced in a bacterial expression system at levels that will be suitable for clinical trials; (ii) LVN can be prepared by a technology that will provide sufficient material for clinical use; and (iii) LVN will demonstrate impressive anticancer efficacy and pharmacological and toxicological properties suitable for clinical translation. The following specific aims and milestones are established for the successful completion of these Phase I studies: Specific aim #1: Prepare a modified version of VN (that has full biological activity and enhanced affinity for integrin ?5a1) 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: Examine initial toxicologic properties of LVN (Milestone 3, months 6-12). Specific Aim #3: Examine efficacy of VN combined with chemotherapy in rodent models of human prostate cancer (PCA). In view of the realization that in the clinic antiangiogenic drugs will need to be used in combination with chemotherapeutic agents or antiangiogenic agents with a different mechanism of action, we will examine effectiveness of the combination of VN with a chemotherapeutic agent used for treatment of PCA, such as docetaxel. For these studies we will employ human PCA subcutaneous and orthotopic xenograft models in vivo. As part of the rodent model studies we will test the activity of LVN +/- androgen ablation +/- chemotherapy against androgen-dependent PCA. We will determine whether there is enhanced antitumor/antiangiogenic efficacy with combination therapy (Milestone 4, months 9-12). Specific Aim #4: Determine if LVN has activity against bone metastases from PCA in rodent models. A major end-of-life issue in PCA is the devastating effect of bone metastases. We will establish rodent models of prostate cancer bone metastases with a luminescent PC cell line which will allow us to determine the efficacy of LVN in combination with androgen ablation+/-chemotherapy in treating existing bone metastases and preventing new bone lesions (Milestone 5, months 6-12). New approaches for the treatment of prostate cancer are needed. Angiogenesis is a critical step for tumor growth and metastasis. The milestones delineated in this application will demonstrate the therapeutic efficacy of LVN alone and in combination with other chemotherapeutic agents in xenograft and bone metastasis rodent models of human prostate cancer. We expect that the proposed studies will identify VN as an anti-cancer agent that may be suitable for further clinical studies in prostate cancer. Lay Language: Prostate cancer is the second leading cause of cancer death of men in the United States. We have identified a natural protein that possesses potent anti- cancer activities. In the development of more effective prostate cancer therapies we have produced a recombinant variant of the natural protein. In this proposal we will show that the recombinant protein has activity equivalent to the natural protein and is amenable to therapeutic use in prostate cancer. We will examine the anti-tumor efficacy of this protein alone and in combination with current prostate cancer therapeutics as well as evaluate the toxicologic properties of the protein. These studies will advance the clinical potential of this novel anticancer protein.
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Institution: MOLECULAR EXPRESS, INC. 13310 S FIGUEROA STREET LOS ANGELES, CA 90061 Fiscal Year: 2007 Department: Project Start: 13-AUG-2007 Project End: 31-JUL-2008 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1