UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My current research is primarily in two areas: (1) angiogenesis and ovarian cancer, and (2) regulation of growth and function of the primate fetal adrenal gland.

In the area of angiogenesis in ovarian cancer, we developed a nude mouse model of advanced human ovarian cancer with ascites. Using this model, we studied a variety of regimens to inhibit angiogenesis, thereby preventing tumor growth. These have included inhibition of phosphatidylinositol-3-kinase (PI3-K), a molecule involved in the signaling of a key angiogenic molecule, vascular endothelial growth factor (VEGF). We have used this PI3-K inhibitor in the presence and absence of the chemotherapeutic agent, paclitaxel, and found marked inhibition of ascites and an ~ 80% reduction in tumor burden. We also have used two inhibitors of VEGF itself, a VEGF monoclonal antibody and a VEGF soluble decoy receptor, the VEGF Trap, again, both in the presence and absence of paclitaxel. Both agents had a marked effect on reduction of ascites and tumor burden when used in combination of paclitaxel, with the VEGF Trap + paclitaxel achieving a striking 98% reduction in tumor burden and virtually complete inhibition of tumor burden. We are currently working on a clinical trial of this combination therapy.

In the fetal adrenal gland, we have identified several growth factors and other peptides that have specific localizations in the different zones of the gland. These have included neural cell adhesion molecule (NCAM), midkine, NovH, SPARC, the low density lipoprotein receptor and others. To obtain the separation of the zones, we have used subtraction hybridization, laser capture microdissection and fluorescent activated cell sorting. To identifiy the genes that encode these proteins, we have used in situ hybridization, northern blotting and other conventional molecular biological techniques. To identify and localize the proteins, we have used immunocytochemistry, western blotting and other techniques. We have been studying the function of these molecules, particularly in regard to cell motility, growth, functional zonation and angiogenesis. We have made a detailed study of the angiogenic factors involved in the extensively vascular fetal adrenal gland essential both for secretion of steroid and catecholaminergic hormones and the ingress of trophic hormones that stimulate steroidogenesis, and we have found that ACTH stimulates both steroidogenesis and angiogenesis in a coordinated fashion.

Selected References

Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB. Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 2002 Nov;161(5):1917-24.

Ratcliffe J, Nakanishi M, Jaffe RB. Identification of definitive and fetal zone markers in the human fetal adrenal gland reveals putative developmental genes. J Clin Endocrinol Metab. 2003 Jul;88(7):3272-7.

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