Paul B. Fisher, Ph.D.

Molecular Basis of Cancer, Cellular Differentiation and Neurodegeneration

The primary goals of our laboratory are to define the molecular and immunological basis of cancer development and progression and the genes and pathways involved in neurodegeneration. Novel cell culture systems and molecular strategies (including the applications of subtraction hybridization, reciprocal subtraction differential RNA display cloning (RSDD), rapid subtraction hybridization (RaSH), antibody and hybridization-based expression cloning and inducible cDNA suppression cloning) are being used to identify and isolate genes critical to the initiation, promotion and progression phases of the oncogenic process. These approaches are also being applied to define astrocyte genes regulated as a consequence of neurodegeneration. Approaches have been developed for cloning full-length genes and evaluating their expression using inducible cell culture and animal models. Employing one technique developed in our laboratory, surface epitope masking (SEM), monoclonal antibodies are being produced that react specifically with known surface expressed molecules (such as the multidrug resistance P-glycoprotein and the human interferon gamma receptor) and unique tumor associated antigens (such as PCTA-1 and BrCar 5.1.3). Our studies will provide insights into the genetic and biochemical changes that mediate carcinogenesis and neurodegeneration and will permit the identification of important cellular targets useful for cancer therapy and preventing or correcting neurodenegerative changes in the brain.

Specific research projects are directed toward (1) determining the molecular basis of progression of the transformed phenotype and the role of the novel gene, progression elevated gene-3 (PEG-3), in this process; (2) identifying, cloning and characterizing genes that mediate growth arrest, terminal cell differentiation and cancer suppression in mammalian cells; (3) identifying, cloning and characterizing genes mediating and suppressing invasion and metastasis; (4) determining the functional roles in vitro and in vivo in animal models of a novel human cancer-related galectin-8, prostate carcinoma tumor antigen-1 (PCTA-1), and the cancer specific growth suppressing and apoptosis-inducing gene, melanoma differentiation associated gene-7 (mda-7), in the development of human malignancies; (5) use of cancer specific promoters to selectively target tumor cells for destruction, the CURE (cancer utilized reporter execution) approach; (6) developing monoclonal antibodies specific for surface expressed and tumor associated antigens. (7) identification and characterization of genes displaying altered expression in human astrocytes as a function of HIV-1 infection and neurodegeneration; and (8) characterization of human glutamate transporter promoters, such as GLT1/EAAT2, and developing high throughput small molecule screening approaches for identifying compounds with neuro-protective properties.

Selected Publications:

• Su, Z.Z., Lin, J., Shen, R., Fisher, P.A., Goldstein, N.I., and Fisher, P.B. Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family. Proc. Natl. Acad. Sci. USA 93: 7252-7257 (1996).

• Kang, D.-c., La France, R., Su, Z.Z., and Fisher, P.B. Reciprocal subtraction differential RNA display (RSDD): an efficient and rapid procedure for isolating differentially expressed gene sequences. Proc. Natl. Acad. Sci. USA 95: 13788-13793 (1998).

• Su, Z.Z., Madireddi, M.T., Lin, J.J., Young, C.S.H., Kitada, S., Reed, J.C., Goldstein, N.I., and Fisher, P.B. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc. Natl. Acad. Sci. USA 95: 14400-14405 (1998).

• Su, Z.Z., Goldstein, N.I., Jiang, H., Wang, M.-N., Duigou, G.J., Young, C.S.H., and Fisher, P.B. PEG-3, a non-transforming progression gene, is a positive regulator of cancer aggressiveness and angiogenesis. Proc. Natl. Acad. Sci. USA 96: 15115-15120 (1999).

• Park, J.S., Carter, S., Reardon, D.B., Schmidt-Ullrich, R.K., Dent, P., and Fisher, P.B. Roles for basal and stimulated p21^{Cip-1/WAF1/MDA6} expression and mitogen activated kinase signaling in radiation-induced cell cycle checkpoint control in carcinoma cells. Mol. Biol. Cell 10: 4231-4246 (1999).

• Jiang, H., Kang, D.-c., Alexandre, D., and Fisher, P.B. RaSH, A rapid subtraction hybridization approach for identifying and cloning differentially expressed genes. Proc. Natl. Acad. Sci. USA 97: 12684-12689 (2000).

• JSimm, M., Su, Z.Z., Huang, E.Y., Chen, Y., Jiang, H., Volsky, D.J. and Fisher, P.B. Cloning of differentially expressed genes in an HIV-1 resistant T cell clone by rapid subtraction hybridization, RaSH. Gene 269: 93-101 (2001).

• Su, Z.Z., Lebedeva, I.V., Gopalkrishnan, R.V., Goldstein, N.I., Stein, C.A., Reed, J.C., Dent, P., and Fisher, P.B. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc. Natl. Acad. Sci. USA, in press (2001).

• Gopalkrishnan, R.V., Kang, D.-C., and Fisher, P.B. Molecular markers and determinants of human prostate cancer metastasis. J. Cell. Physiol., in press (2001).