The thrust of the Laboratory of Urological Oncology is the study of the cell biology of urological cancers at a molecular level and the translation of this understanding into improved diagnostics and therapeutics. Recombinant DNA and hybridoma technology provide the basic tools utilized to accomplish the molecular dissection of these cancers.


For example, in renal cancer, we have generated and characterized the largest panel of established human renal cancer cell lines and monoclonal antibodies (mAbs) to kidney differentiation antigens. In most cases, the chromosomal location of the antigens has been mapped and, in several cases, the gene cloned and the function defined. This work has allowed the molecular phenotyping of renal cancer and more precise understanding of the histogenesis of the disease. We have shown, for the first time, that 30% of renal cancers derive from the proximal convoluted tubule, 20% from the straight portion of the proximal tubule, and 50% from a proximal tubular progenitor cell. It has also allowed an understanding that there are molecular subtypes of renal cancer and that these subtypes have differing patterns of clinical behavior. With colleagues at the Ludwig Institute for Cancer Research (at Memorial Sloan-Kettering Cancer Center), we conducted clinical trials with these mAbs in patients with renal cancer. These studies have demonstrated the ability of mAbs, most notably mAb G250, to specifically and sensitively target disseminated renal cancer sites in patients. This antibody is now in an international phase III registration trial. The G250 antigen?carbonic anhydrase IX?is regulated by the HIF (hypoxia inducible) pathway and has been shown by several groups to have prognostic significance.


In prostate cancer, we developed the first series of mAbs to the extracellular domain of prostate specific membrane antigen (PSMA). PSMA is the most well-established, prostate cancer-restricted, cell membrane antigen yet defined. These mAbs were the first to specifically bind to viable PSMA-expressing cells. We demonstrated, for the first time, that PSMA and mAbs that bind PSMA, are internalized via an endocytic pathway. We also demonstrated that PSMA is expressed by neovascular endothelial cells of all solid tumors but not by normal vascular endothelial cells. We selected one of our mouse antibodies, designated J591, and de-immunized it by genetic engineering techniques. The de-immunized antibody has been used in multiple clinical trials that have demonstrated success in specifically targeting metastatic prostate cancers as well as the neovasculature of other solid tumors. This antibody was licensed to industry for clinical development. Radiolabeled and cytotoxin-conjugated J591 are now in multi-center phase II trials.