Department Affiliation: Primary: Oncology; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Columbia College of Physicians and Surgeons, Columbia University
Rank: Associate Professor
Telephone Number: 410-502-3941
Fax Number: 410-614-8397
E-mail address: denmesa@jhmi.edu
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.
Representative Publications:
- Denmeade, S.R., Jakobsen, C., Janssen, S., Khan, S.R., Lilja, H., Christensen, S.B. and Isaacs, J.T. Prostate-Specific Antigen (PSA) Activated Thapsigargin Prodrug as Targeted Therapy for Prostate Cancer, JNCI 95:990-1000, 2003. Pub Med Reference
Janssen, S., Rosen, D.M., Ricklis, R.M., Dionne, C.A., Lilja, H., Christensen, S.B., Isaacs, J.T., Denmeade, S.R. Pharmacokinetics, biodistribution and antitumor Efficacy of a human glandular kallikrein 2 (hK2) -activated thapsigargin prodrug. Prostate. 66:358-68, 2006. Pub Med Reference
Aggarwal, S., Harden, J.L., Denmeade, S.R. Synthesis and screening of a random dimeric peptide library using one-Bead-one dimer combinatorial approach. Bioconj Chem. 17:335-40, 2006. Pub Med Reference
Aggarwal, S., Singh, P., Topaloglu, O., Isaacs, J.T., Denmeade, S.R. A dimeric peptide that binds selectively to prostate-specific membrane antigen and inhibits its enzymatic activity. Cancer Res. 66:9171-7, 2006. Pub Med Reference
Williams, S.A., Singh, P., Isaacs, J.T., Denmeade, S.R. Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer? Prostate. 67:312-29, 2007. Pub Med Reference
Williams, S.A., Merchant, R.F., Garrett-Mayer, E., Isaacs, J.T., Buckley, J.T., Denmeade, S.R. A prostate-specific antigen-activated channel forming toxin as therapy for prostatic disease. J Natl Cancer Inst, 2007;99:376-85. Pub Med Reference
Collins, C., Carducci, M.A., Eisenberger, M.A., Isaacs, J.T., Partin, A.W., Pili, R., Sinibaldi, V.J., Walczak, J.S., Denmeade, S.R. Preclinical and Clinical Studies With the Multi-Kinase Inhibitor CEP-701 as Treatment for Prostate Cancer Demonstrate the Inadequacy of PSA Response as a Primary Endpoint. Cancer Biol Ther. Jun 5;6(9), 2007. [Epub ahead of print] Pub Med Reference
Chandran SS, Nan A, Rosen DM, Ghandehari H, Denmeade SR. A Prostate-Specific Antigen (PSA)-activated HPMA copolymer prodrug as dual-targeted therapy for prostate cancer. Mol Cancer Therapeutics. 6:2928-37, 2007. Pub Med Reference
Singh, P., Williams, S., Shah, M., Lectka, T., Pritchard, G., Isaacs, J.T., Denmeade, S.R. Mechanistic insights into the inhibition of Prostate-Specific Antigen (PSA) by ß-lactam class compounds. Proteins. 70:1416-28, 2008. Pub Med Reference
Other graduate programs in which Dr. Denmeade participates:
