Our laboratory has cloned and characterized the expression of the mRNA encoding prostate-specific membrane antigen (PSMA); sequenced human and mouse PSMA DNA; generated PSMA knockout mice;identified the PSMA enhancer: established it as a peptide carboxypeptidase with preferred substrates of polygammaglutamated folate and N-acetylaspartylglutamate (NAAG).
We observed that PSMA is strongly upregulated in cancer and observed that PSMA is also strongly expressed on all human tumor neovasculature. Our laboratory is examining ways to target PSMA both for therapy and for imaging.
In addition to PSMA as a target for therapy in cancer, PSMA expression has been studied in the brain and is known by neurobiologists as NAALADASE and serves to inactivate the brain peptide NAAG. NAAG has been identified to play a major role in brain function as a ligand for metabotropic glutamate receptor 3 and is related to short term memory consolidation and other aspects of brain function. Because PSMA (NAALADASE) is the major mechanism of NAAG inactivation, We are working with collaborators to establish the role of PSMA (NAALADASE) using our knockout models for establishing the modulating impact of NAAG function in the CNS.
We are also examining therapeutic approaches to other genito-urinary tumors such as bladder cancer and kidney cancer. In kidney cancer we are examining the mechanism of action of a recently identified novel plant based toxin that has a strong specificity for kidney cancer identified as Englerin A.
In vitro and in vivo responses of advanced prostate tumors to PSMA ADC an auristatin-conjugated antibody to prostate-specific membrane antigen. Wang X, Ma D, Olson WC, Heston WD. Mol Cancer Ther. 10: 1728-1739, 2011.
Role of TMPRSS2-ERG gene fusion in negative regulation of PSMA expression. Yin L, Rao P, Elson P, Ittmann M, Heston WD: PLOS one 6: e21319 epub 2011.
Sunitinib malate provides activity against murine bladder tumor growth and invasion in a preclinical orthotopic model. Chan ES, Patel ER, Hansel DE, Larchian WA, Heston WD: Urology 80: 736 1-5, 2012.
NAAG peptidase inhibitors and deletion of NAAG peptidase gene enhance memory in novel object recognition test. Janczura KJ, Olszewski RT, Bzdega T, Bacich DJ, Heston WD, Neale JH: Eur J Pharmacol Nov 29 2012 epub ahead of print.