Warren Heston, Ph.D.
Department of Cancer Biology
Prostate cancer, tumor targeting, imaging
Our laboratory has cloned and initially characterized the expression of the mRNA encoding prostate-specific membrane antigen (PSMA); sequenced human and mouse PSMA DNA; generated PSMA-knockout and transgenic mice expressing PSMA in their prostates; identified and sequenced the closely related PSMA-like gene; identified the PSMA enhancer and evaluated a potential means of prodrug activation in gene therapy strategies; observed that PSMA is strongly expressed on all human tumor neovasculature; developed RT-PCR methods of detecting circulating human prostate cells; identified PSMA as a folate hydrolase and glutamate carboxypeptidase; elucidated the role of glycosidation and dimerization in PSMA’s enzymatic activity; and shown PSMA’s attenuation of cell invasiveness.
PSMA is strongly expressed on nearly all prostate cancer cells and on blood vessels in all solid tumors. Because prostate cancer is a leading cause of death in men, it is crucial that we pursue PSMA as a prime target for tumor treatment.
A number of fully human or humanized anti-PSMA antibodies linked to toxins are under clinical investigation as targeting vectors for cancer treatment, whether prostate cancer tumors or the tumor blood vessels of any other solid tumor.
We are also developing low-molecular-weight PSMA ligands for imaging. Thus our current focus is find means of targeting PSMA for therapy and/or imaging.
Chang, S.S., Gaudin, P.B., Reuter, V.E., O'Keefe, D.S., Bacich, D.J., and Heston, W.D.W. (1999). Prostate-specific membrane antigen: much more than a prostate cancer marker. Mol. Urol. 3, 313-320.
Chang, S.S., O'Keefe, D.S., Bacich, D.J., Reuter, V.E., Heston, W.D., and Gaudin, P.B. (1999). Prostate-specific membrane antigen is produced in tumor- associated neovasculature. Clin. Cancer Res. 5, 2674-2681.
Chang, S.S., Gaudin, P.B., Reuter, V.E., and Heston, W.D. (2000). Prostate-specific membrane antigen: present and future applications. Urology 55, 622-629.
Pinto, J.T., Qiao, C., Xing, J., Suffoletto, B.P., Schubert, K.B., Rivlin, R.S., Huryk, R.F., Bacich, D.J., and Heston, W.D. (2000). Alterations of prostate biomarker expression and testosterone utilization in human LNCaP prostatic carcinoma cells by garlic- derived S-allylmercaptocysteine. Prostate 45, 304-314.
Gong, M.C., Chang, S.S., Watt, F., O'Keefe, D.S., Bacich, D.J., Uchida, A., Bander, N.H., Reuter, V.E., Gaudin, P.B., Molloy, P.L., Sadelian, M., and Heston, W.D.W. (2000). Overview of evolving strategies incorporating prostate-specific membrane antigen as target for therapy. Mol. Urol. 4, 217-222; discussion 223.
Horiguchi, Y., Larchian, W.A., Kaplinsky, R., Fair, W.R., and Heston, W.D.W. (2000). Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model. Gene Ther. 7, 844-851.
O'Keefe, D.S., Uchida, A., Bacich, D.J., Watt, F.B., Martorana, A., Molloy, P.L., and Heston, W.D.W. (2000). Prostate-specific suicide gene therapy using the prostate- specific membrane antigen promoter and enhancer. Prostate 45, 149-157.
Bacich, D.J., Pinto, J.T., Tong, W.P., and Heston, W.D.W. (2001). Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen/NAALADase/folate hydrolase. Mamm. Genome 12, 117-123.
O'Keefe, D.S., Bacich, D.J., and Heston, W.D.W. (2001). Prostate specific membrane antigen. In Prostate cancer: biology, genetics, and the new therapeutics, Chung, L. W. K., Isaacs, W. B. and Simons, J. W. eds., (Totowa, N.J.: Humana Press) pp. 307-326.
Tasch, J., Gong, M., Sadelain, M., and Heston, W.D.W. (2001). A unique folate hydrolase, prostate-specific membrane antigen (PSMA): a target for immunotherapy? Crit. Rev. Immunol. 21, 249-261.
Chang, S.S., Reuter, V.E., Heston, W.D., and Gaudin, P.B. (2001). Metastatic renal cell carcinoma neovasculature expresses prostate-specific membrane antigen. Urology 57, 801-805.
Uchida, A., O'Keefe, D.S., Bacich, D.J., Molloy, P.L., and Heston, W.D.W. (2001). In vivo suicide gene therapy model using a newly discovered prostate-specific membrane antigen promoter/enhancer: a potential alternative approach to androgen deprivation therapy. Urology 58, 132-139.
Chang, S.S., and Heston, W.D.W. (2002). The clinical role of prostate-specific membrane antigen (PSMA). Urol. Oncol. 7, 7-12.
Rajasekaran, S.A., Anilkumar, G., Oshima, E., Bowie, J.U., Liu, H., Heston, W., Bander, N.H., and Rajasekaran, A.K. (2003). A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol. Biol. Cell 14, 4835-4845.
Ghosh, A., and Heston, W.D.W. (2003). Effect of carbohydrate moieties on the folate hydrolysis activity of the prostate specific membrane antigen. Prostate 57, 140-151.
Schulke, N., Varlamova, O.A., Donovan, G.P., Ma, D., Gardner, J.P., Morrissey, D.M., Arrigale, R.R., Zhan, C., Chodera, A.J., Surowitz, K.G., Maddon P.J., Heston W.D., and Olson W.C. (2003). The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. Proc. Natl. Acad. Sci. U. S. A. 100, 12590-12595.
Chang, S.S., Bander, N.H., and Heston, W.D.W. (2004). Biology of PSMA as a diagnostic and therapeutic target. In Management of prostate cancer, Klein, E. A. ed., (Totowa, NJ: Humana Press) pp. 609-630.
O'Keefe, D.S., and Heston, W.D.W. (2004). Clearing up the confusion over the glutamate carboxypeptidase II gene. Am. J. Med. Genet. 130A, 327-330.
O'Keefe, D.S., Bacich, D.J., and Heston, W.D.W. (2004). Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene. Prostate 58, 200-210.
Ghosh, A., and Heston, W.D.W. (2004). Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J. Cell. Biochem. 91, 528-539.
Ghosh, A., Wang, X., Klein, E., and Heston, W.D.W. (2005). Novel role of prostate-specific membrane antigen in suppressing prostate cancer invasiveness. Cancer Res. 65, 727-731.
Foss, C.A., Mease, R.C., Fan, H., Wang, Y., Ravert, H.T., Dannals, R.F., Olszewski, R.T., Heston, W.D., Kozikowski, A.P., and Pomper, M.G. (2005). Radiolabeled small-molecule ligands for prostate-specific membrane antigen: in vivo imaging in experimental models of prostate cancer. Clin. Cancer Res. 11, 4022-4028.
Gade, T.P.F., Hassen, W., Santos, E., Gunset, G., Saudemont, A., Gong, M.C., Brentjens, R., Zhong, X.S., Stephan, M., Stefanski, J., Lyddane C., Osborne J.R., Buchanan I.M., Hall S.J., Heston W.D., Riviere I., Larson S.M., Koutcher J.A., and Sadelain M. (2005). Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res. 65, 9080-9088.
Ghosh, A., and Heston, W.D.W. (2005). Understanding prostate-specific membrane antigen and its implication in prostate cancer. In Oncogenomics handbook, LaRochelle, W. J., and Shimkets, R. A. eds., (Totowa, N.J.: Humana Press) pp. 597-615.
Horinaga, M., Harsch, K.M., Fukuyama, R., Heston, W., and Larchian, W. (2005). Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model. Urology 66, 461-466.
Conway, R.E., Petrovic, N., Li, Z., Heston, W., Wu, D., and Shapiro, L.H. (2006). Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction. Mol. Cell. Biol. 26, 5310-5324.
Jayaprakash S, et al. Design and synthesis of a PSMA inhibitor-doxorubicin conjugate for targeted prostate cancer therapy. Chem Med Chem 2006;1:299-302. Durso RJ, et al. A novel alphavirus vaccine encoding prostate-specific membrane antigen elicits potent cellular and humoral immune responses. Clin Cancer Res 2007;13:3999-4008.
Wang X, et al. Targeted treatment of prostate cancer. J Cell Biochem 2007;102:571-9.
Yao V, Parwani A, Maier C, Heston WDW, Bacich DJ: Moderate expression of prostate-specific membrane antigen, a tissue differentiation antigen and folate hydrolase, facilitates prostate carcinogenesis. Cancer Res 68: 9070-9077, 2008.
Patel A, Chan E, Smith A, Klein E, Heston WD, Larchian WR: Transabdominal microultrasound imaging of a bladder cancer in a mouse model: a validation study. Urology 75: 799-804, 2010.
Samplaski M, Heston WDW, Hansel D: PSMA expression in bladder cancer subtypes and tumor associated neovasculature. Modern Pathology. In press. Goc A, Al-Husein B, Kochuparambil ST, Liu J, Heston W, Somanath PR: P13 kinase signaling pathways in the regulation of prostate cancer. Int J Oncol 38: 267-277, 2011.
Yang H, Kim C, Kim MJ, Schwendener RA, Alitalo K, Kim I, Kim WJ, Koh GY: Soluble vascular endothelial receptor 3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer. Mol Cancer. 10:36-2011.
Chan ES, Patel AR, Larchian WA, Heston WD: In-vivo targeted contrast enhanced micro-ultrasound to measure intratumor perfusion and vascular endothelial growth factor receptor 2 expression in a mouse orthotopic bladder cancer model. J Urol. 185: 2359-2365, 2011.
Wang, Y. Romigh T, He X, Tan MH, Orloff MS, Silverman RH, Heston WD, Eng C: Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene 2011 (May epub).
Yin L, Rao P, Elson P, Wang J, Ittmann M, Heston WDW: Role of TMPRSS2-ERG gene fusion in negative regulation of PSMA expression. PLoS One 6: 1-6, e21319, 2011.
Nakajima T, Mitsunaga M, Bander NH, Heston WD, Choyke PL, Kobayashi H: Targeted Activatable, In Vivo Fluorescence Imaging of Prostate-Specific Membrane Antigen (PSMA)-Positive Tumors Using The Quenched Humanized J591 Antibody-ICG Conjugate. Bioconjugate Chemistry (Just accepted- 2011).
Wang X, Ma D, Olson WC, Heston WDW: In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin conjugated antibody to prostate specific membrane antigen. Mol. Cancer Therap. 2011, in press.