): The two objectives of this application are to support the training of a clinician as a medical scientist and to develop novel gene therapy strategies for human prostate cancer (PCA). Dr. Carducci aspires to a career of independent scholarship in oncology. This mentored research award will provide Dr. Carducci with detailed molecular laboratory training in the Gene Therapy and Experimental Therapeutics laboratory of the Johns Hopkins Oncology Center, under Dr. Jonathan Simons, the award sponsor. The rising incidence of prostate cancer in the U.S. demands new strategies for its treatment and prevention. The Simons' laboratory focuses on the development of novel, yet rational molecular-based approaches to the eradication of hormone refractory PCA. This laboratory has formulated and demonstrated the feasibility of GM-CSF gene therapy for human PCA. The first N.I.H. RAC-approved Phase I trial of GM-CSF gene therapy for human PCA is underway at Johns Hopkins. Autologous tumor vaccines engineered to secrete the GM-CSF cytokine, using the retroviral vector MFG, demonstrate anti-tumor effects in a rat PCA cancer model. Dr. Carducci has generated preliminary data suggesting efficacy of this form of gene therapy is related to the amount and pharmacokinetics of GM-CSF secretion. In Phase I of this award, Dr. Carducci will refine further and complete the pharmacokinetic evaluation of this form of therapy for translation to the clinical testing. Multiple, well-controlled animal studies evaluating the pharmacodynamics of GM-CSF gene therapy will be conducted using molecular techniques such as vector construction, Southern and Northern blotting, etc. Experiments will include the rigorous comparison of MFG to other replication-defective viral vectors, specifically adenoviruses. Dr. Carducci will work closely with their collaborator, Dr. Richard Mulligan, on the molecular aspects of these vectors and the development of new vector systems. These collaborative meetings will complement the didactic program in molecular biology which Dr. Carducci has set up. Dr. Elizabeth Jaffee will assist Dr. Carducci in the immunologic evaluation of GM-CSF gene therapy in the rat PCA models. Dr. Carducci plans to focus, during Phase II, on screening and testing cytotoxic cDNAs from toxin-secreting organisms in the biosphere for development of cytoreductive gene therapy strategies for PCA. Using replication-defective adenoviruses, prostate specific promoters, and the most potent of the cytotoxic cDNAs against PCA cell lines, the next generation of preclinical gene therapy trials can be developed for translation to human studies. The research plan is novel, yet fundamentally important to developing new strategies for the therapy of PCA.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Cancer Research Manpower and Education Review Committee (CRME)
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Verheul, Henk M W; Qian, David Z; Carducci, Michael A et al. (2007) Sequence-dependent antitumor effects of differentiation agents in combination with cell cycle-dependent cytotoxic drugs. Cancer Chemother Pharmacol 60:329-39
Nelson, Joel B; Nabulsi, Azmi A; Vogelzang, Nicholas J et al. (2003) Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J Urol 169:1143-9
Carducci, M A; Gilbert, J; Bowling, M K et al. (2001) A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res 7:3047-55
Pili, R; Kruszewski, M P; Hager, B W et al. (2001) Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res 61:1477-85