The main research goals of Dr. Denmeade’s 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 activation by these cancer selective targets while avoiding or minimizing systemic toxicity; and (3) to develop new hormonal therapies for prostate cancer based on underlying biology.
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, Dr. Denmeade and his lab 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 they 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, they 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.
Clinical Trial Keywords:
kidney cancer, bladder cancer, prostate cancer
Schweizer MT, Antonarakis ES, Wang H, Ajiboye AS, Spitz A, Cao H, Luo J, Haffner MC, Yegnasubramanian S, Carducci MA, Eisenberger MA, Isaacs JT, Denmeade SR. Effect of bipolar androgen therapy for asymptomatic men with castrate-resistant prostate cancer: Results from a pilot clinical study. Sci Trans Med. 2014: In Press
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, DeMarzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38.
Manning ML, Williams SA, Jelinek CA, Kostova MB, Denmeade, SR. Proteolysis of Complement Factors iC3b and C5 by the Serine Protease Prostate-Specific Antigen (PSA) in Prostatic Fluid and Seminal Plasma. J Immunology 2013;190(6):2567-74.
Elhilali MM, Pommerville P, Yocum RC, Merchant R, Roehrborn CG, Denmeade SR. Prospective, Randomized, Double-Blind, Vehicle-Controlled, Multicenter Phase IIb Clinical Trial of the Pore- Forming Protein PRX302 for Targeted Treatment of Symptomatic Benign Prostatic Hyperplasia. J Urol. 2013 Apr;189(4):1421-6.
Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel B, Demarzo AM, Wilding G, Carducci MA, Dionne CA, Møller JV, Nissen P, Christensen SB, Isaacs JT. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Sci Transl Med. 2012 Jun 27;4(140):140ra86.