Unlike organ-confined disease, metastatic prostate cancer is incurable. Chemotherapy can be toxic; while palliative therapies do not prevent disease progression. The alpha5beta1 integrin receptor is an attractive therapeutic target. While it is widely expressed, inactive alpha5beta1 does not mediate invasion. However, activated alpha5beta1 is found specifically on prostate cancer cells, and functions in invasion and metastasis, as well as in survival. Since activation causes significant structural rearrangements, like changes in disulfide bonding patterns in both the alpha5 and the beta1 subunits, agents may be designed to interact only with activated alpha5beta1 receptors. Because of their specificity, we hypothesize that these agents will be potent inhibitors of prostate cancer metastasis, while having minimal toxic effects on healthy tissues. Our published and preliminary results suggest that the PHSCN peptide binds activated alpha5beta1 specifically, thereby blocking invasion and inducing apoptosis in vitro, and preventing growth, metastasis and tumor recurrence in preclinical models of prostate cancer. Moreover in a recent Phase I clinical trial, systemic PHSCN monotherapy was well tolerated, and metastatic disease failed to progress for 4-14 months in 38% of patients receiving it. Here, we propose to enhance the development of PHSCN as a therapeutic agent by defining its target on alpha5beta1 integrin. We have recently developed a more potent derivative of PHSCN: the PHSCN-polylysine dendrimer. Thus, we also propose to compare the PHSCN peptide and the PHSCN-dendrimer as inhibitors of invasion and survival in metastatic human prostate cancer cell lines. Finally, we propose to quantitate invasion and metastasis inhibition, and apoptosis induction in primary tumors and in lung and liver metastases of human prostate cancer in nude mice. The proposed research may have a major impact on public health because prostate cancer is the most common noncutaneous neoplasm, and the second leading cause of cancer death in American men; moreover, its incidence is increasing. Furthermore, it is especially prevalent in African American men. Also, 50% to 90% of newly diagnosed prostate cancer patients already have locally advanced or metastatic disease. Thus, an effective, well-tolerated, nontoxic therapy that prevents prostate cancer progression for long periods of time could be very beneficial to many patients. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Forry, Suzanne L
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Veine, Donna M; Yao, Hongren; Stafford, Daniel R et al. (2014) A D-amino acid containing peptide as a potent, noncovalent inhibitor of ?5?1 integrin in human prostate cancer invasion and lung colonization. Clin Exp Metastasis 31:379-93
Yao, Hongren; Zeng, Zhao-Zhu; Fay, Kevin S et al. (2011) Role of ?(5)?(1) Integrin Up-regulation in Radiation-Induced Invasion by Human Pancreatic Cancer Cells. Transl Oncol 4:282-92
Yao, Hongren; Veine, Donna M; Zeng, Zhao-Zhu et al. (2010) Increased potency of the PHSCN dendrimer as an inhibitor of human prostate cancer cell invasion, extravasation, and lung colony formation. Clin Exp Metastasis 27:173-84