Ching Y Wang, PhD
Education & Fellowships
- PhD: Auburn University, Alabama, 1970
Antibody Therapy for Prostate Cancer
Prostate cancer has the highest cancer incidence and the second leading cause of cancer death in men. Response to androgen ablation in early-stage disease is temporary and palliative in most cases. Of the patients diagnosed with small clinically palpable lesions, 30 to 35% develop metastases. Traditional chemotherapy and radiation therapy have very limited efficacy for metastatic disease. New treatment modalities are clearly needed.
Prostate-specific membrane antigen (PSMA) has been targeted for immunotherapy of this cancer because it is relatively specific for prostate epithelial cells and its expression is upregulated during malignant process. PSMA is a transmembrane protein with folate hydrolase activity. Its biological function in prostate epithelium is not known. Using computer-aided analyses, we have identified several antigenic epitopes in the extracellular domain of PSMA. We have prepared oligopeptides for immunization and prepared monoclonal antibodies against these specific epitopes. Preliminary results suggest that these antibodies are cytotoxic to the PSMA-positive human prostate cancer but not to PSMA-negative cancer cells.
Our investigation is now focused on (1) humanization of the monoclonal antibodies, (2) preparation of toxin-conjugated antibodies, and (3) mechanisms of antitumor activity by these antibodies and immunotoxins. The human antibodies and immunotoxins have potential clinical use.
K. Kuratsukuri, C. Y. Wang, T. Sone, N. Nishisaka, R. F. Jones and G. P. Haas. Induction of antibodies against prostate-specific membrane antigen (PSMA) by vaccination with a PSMA DNA vector. Eur. Urol. 120:1-7, 2002.
K. Kuratsukuri, T. Sone, C. Y. Wang, N. Nishisaka, R. F. Jones and G. P. Haas. Inhibition of prostate-specific membrane antigen (PSMA)-positive tumor growth by vaccination with either full-length or the C-terminal end of PSMA. Int. J. Cancer (in press), 2002.
Kinoshita, Y., Kuratsukur, K., Newman, N., Rovito, P.M.,Jr., Kaumaya, P.T.P, Wang, C.Y., and Haas, G.P. Targeting epitopes of prostate-specific membrane antigen for antibody therapy of prostate cancer. Prostate Cancer & Prostatic Diseases. In press, 2005.
Mechanisms of Urinary Bladder Tumorigenesis. With R. Jones
Aminoheterocycles are abundant in cooked foods, cigarette smoke and ambient air. They are N-hydroxylated and conjugated with glucuronic acid in the liver, then excreted as N-hydroxy-N-glucuronide metabolites (N-OH-N-GI) through biliary and urinary routes. These metabolites can be activated, following deconjugation, by esterification to yield electrophiles that covalently bind predominantly to the deoxyguanosine residues of DNA.
The specific aims of this project are to answer the questions: (1) Are the N-OH-N-GI metabolites of these aminoheterocycles hydrolyzable in neutral solution or susceptible to cleavage by beta -gluc-uronidase? (2) Are their N-OH metabolites activated by urothelial cells of human and other species? (3) Do their N-OH-N-GI metabolites induce urothelial tumors in rat and human urothelial tissue? Are only those hydrolyzable in neutral solution carcinogenic for urinary bladder?
Mechanistic Approaches to Carcinogenesis.
Aromatic amines are believed to induce tumors in humans and experimental animals. The formation of N-acetoxyarylamines has been implicated as the latter metabolic activation step that is crucial to the carcinogenic and mutagenic activities of many of these agents. In the rat, mouse and rabbit, and perhaps other species such as the human and hamster, the terminal activation reaction, O-acetylation, involves the transfer of an acetyl group to the hydroxylamine from either acetyl coenzyme A or an arylhydroxamic acid. The same enzyme is also capable of N-acetylation to yield arylacetamides or arylhydroxamic acids from arylamines or arylhydroxylamines, respectively. The N-, O- and N,O-acetylation activities of the enzymes from different species vary in their rates and relative abilities to carry out these reactions. These differences are significant determinants of the susceptibilities of the target organs of the aromatic amines. The objective of this project is to explore the molecular features responsible for the differences in activation by O-acetylation, and, consequently, how these factors may influence the carcinogenic and mutagenic responses to these agents.