Experimental Therapeutics

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Robert C. Bast, Jr., MD Research Interests: Signal transduction, ovarian neoplasms, breast neoplasms, biological markers, tumor suppressor genes

With Drs. Yinhua Yu and Robert Luo (this department), we have identified a novel ras-related growth regulatory gene that is expressed in normal ovarian and breast epithelial cells but not in the majority of ovarian and breast cancer cells. The ARHI (NOEY2) gene is imprinted during normal development, is monoallelically expressed, and maps to chromosome 1p31. Expression of the one functional ARHI allele can be downregulated by deletion (LOH in 40% of breast and ovarian cancers), methylation of CpG Islands (10% of breast cancers), and upregulation of free E2F1 and E2F4. Re-expression of ARHI inhibits the growth, motility, and invasiveness of cancer cells that fail to express the gene. ARHI induces p21, downregulates cyclin D1, blocks signaling though the Ras/mitogen-activated protein, activates c-Jun N-terminal kinase, and promotes apoptosis through a novel calpain-dependent, caspase-independent mechanism. ARHI binds to STAT3, decreasing its translocation to the nucleus and inhibiting its binding to DNA STAT response elements. Expression of human ARHI in transgenic mice produces small stature and inhibits postpartum lactation. The potential for using ARHI in gene therapy in combination with cytotoxic drugs is currently being evaluated.

The tyrosine kinase growth factor receptors provide novel targets for therapy. Specific monoclonal antibodies have been used to inhibit growth of breast and ovarian cancer cells that overexpress HER2, including trastuzumab (Herceptin) and other reagents. Mechanistic studies of antibody-mediated growth inhibition with Drs. Lawrence Le (this department) and Gordon Mills (Department of Molecular Therapeutics) have implicated posttranslational upregulation of p27, inactivation of AKT, and transcriptional downregulation of genes affecting the cell cycle, DNA repair regulation, and drug sensitivity. Many of the changes in gene expression are mediated by signaling through AKT. Trastuzumab decreases the expression of the angiogenic factors VEGF and IL-8 and upregulates thrombospondin, an inhibitor of angiogenesis. Studies of the interaction of Herceptin and taxanes have implicated modulation of the G2/M checkpoint in additive or synergistic toxicity. The role of the ligand heregulin has also been explored in cancer cells that overexpress HER2. Heregulin can induce apoptosis, differentiation, and cell cycle arrest in G2/M. Heregulin-induced apoptosis is mediated by downregulation of BCL2 and activation of caspase 7 and can be potentiated by impairment of protein kinase C alpha activity.

Our group has developed and evaluated several ovarian tumor markers, including CA125, OVX1, and macrophage colony-stimulating factor, that have either proved useful for monitoring the course of patients with known epithelial ovarian cancer or shown promise for its early detection. At present, we are collaborating with Drs. Karen Lu (Department of Gynecologic Oncology), Jinsong Liu (Department of Pathology), Dan Chang (Johns Hopkins University, Baltimore MD), and Gordon Mills to develop new markers for early detection of ovarian cancer and with Drs. Steven Skates (Harvard Medical School, Boston, MA) and Zhen Zhang (Johns Hopkins University) to develop novel methods for estimating the risk of ovarian cancer by monitoring multiple markers over time. Novel markers have been identified using gene expression array and proteomic and lipomic analysis. Neural network and mixed multivariate analysis has been used to combine data for multiple markers, improving sensitivity for early detection without losing specificity. A screening trial has been initiated in women at conventional risk of developing ovarian cancer that uses monitoring over time with a CA125 algorithm.

Selected Publications
Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci USA 96:214-219, 1999

Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN, LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC. Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. Cancer Res 62:7264-7272, 2002

Le XF, Claret FX, Lammayot A, Tian L, Deshpande D, LaPushin R, Tari AM, Bast RC Jr. The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J Biol Chem 278:23441-23450, 2003

Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, Ramoth LR, Rosen DG, Liu J, Hellstrom I, Smith D, Hartmann L, Fishman D, Berchuck A, Schmandt R, Whitaker R, Gershenson DM, Mills GB, Bast RC Jr. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res 10:3291-3300, 2004

Zhang Z, Bast RC Jr, Yu Y, Li J, Sokoll LJ, Rai AJ, Rosenzweig JM, Cameron B, Wang YY, Meng XY, Berchuck A, Van Haaften-Day C, Hacker NF, de Bruijn HW, van der Zee AG, Jacobs IJ, Fung ET, Chan DW. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64:5882-5890, 2004

Additional Information:

Department:	Experimental Therapeutics
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Division/Section:	Cancer Medicine
Last Updated:	05/30/2006