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School of Medicine
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Department Affiliation: Primary: Oncology; Secondary: Pharmacology and Molecular Sciences, Urology, Chemical and Biomolecular Engineering
Degree: M.D., Columbia College of Physicians and Surgeons, Columbia University
Telephone Number: 410-955-8875
Fax Number: 410-614-8397
E-mail address: firstname.lastname@example.org
School of Medicine Address: The Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231
Targeted therapies for cancer; Prodrugs; Protoxins, Protease biology; Protease inhibitors, Cancer imaging
The main research goals of my laboratory are: (1) to identify and study the biology of novel cancer selective targets whose enzymatic function can be exploited for therapeutic and diagnostic purposes; (2) to develop methods to target novel agents for activiation by these cancer selective targets while avoiding or minimizing systemic toxicity; (3) to develop novel agents for imaging cancer sites at earliest stages. To accomplish these objectives the lab has originally focused on the development of prodrugs or protoxins that are inactive when given systemically via the blood and only become activated by tumor or tissue specific proteases present within sites of tumor. Using this approach, we are developing therapies targeted for activation by the serine proteases prostate-specific antigen (PSA), human glandular kallikrein 2 (hK2) and fibroblast activation protein (FAP) as well as the membrane carboxypeptidase prostate-specific membrane antigen (PSMA). One such approach developed in the lab consists of a potent bacterial protoxin that we have reengineered to be selectively activated by PSA within the Prostate. This PSA-activated toxin is currently being tested clinically as treatment for men with recurrent prostate cancer following radiation therapy. In a related approach, a novel peptide-cytotoxin prodrug candidate that is activated by PSMA has been identified and is this prodrug candidate is now entering early phase clinical development. In addition, we have also identified a series of potent inhibitors of PSA that are now under study as drug targeting and imaging agents to be used in the treatment and detection of prostate cancer.
- Aggarwal, S., Brennen, W.N., Kole, T.P., Schneider, E., Topaloglu, O., Yates, M., Cotter, R.J., Denmeade, S.R. Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites. Biochemistry. 2008; 47:1076-86. Pub Med Reference
Chandran, S.S., Banerjee, S.R., Mease, R.C., Pomper, M.G., Denmeade, S.R. Characterization of a targeted nanoparticle functionalized with a urea-based inhibitor of Prostate-Specific Membrane Antigen (PSMA). Cancer Biol Ther. 2008; 7: 974-982. Pub Med Reference
LeBeau, A.M., Singh, P., Isaacs, J.T., Denmeade, S.R. Potent and selective peptidyl-boronic acid inhibitors of the serine protease prostate-specific antigen (PSA). Chem Biol. 2008; 15:665-674. Pub Med Reference
LeBeau, A.M., Singh, P., Isaacs, J.T., Denmeade, S.R. Prostate-specific antigen is a "chymotrypsin-like" serine protease with unique P1 substrate specificity. Biochemistry. 2009; 48:3490-6. Pub Med Reference
LeBeau, A.M., Brennen, W.N., Aggarwal, S., Denmeade, S.R. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther. 2009; In Press, epub May 5. Pub Med Reference
Williams, S.A., Xu, Y., De Marzo, A.M., Isaacs, J.T., Denmeade, S.R. Prostate-specific antigen (PSA) is activated by KLK2 in prostate cancer ex vivo models and in prostate-targeted PSA/KLK2 double transgenic mice. Prostate. 2010; 70:788-96. Pub Med Reference
LeBeau, A.M., Kostova, M., Craik, C., Denmeade, S.R. Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer. Biological Chemistry, In Press, 2010 Pub Med Reference
Denmeade, S.R., Isaacs, J.T. Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010; 70:1600-7. Pub Med Reference
Williams, S.A., Jelinek, C.A., Litvinov, I., Cotter, R.J., Isaacs, J.T., Denmeade, S.R. Enzymatically active prostate-specific antigen promotes growth of human prostate cancers. Prostate. 2011 Mar 10. [Epub ahead of print] Pub Med Reference
Other graduate programs in which Dr. Denmeade participates: