In the Signaling Session, Dr. Dan Theodorescu, UVA discussed mechanisms of signal transduction in bladder cancer. The goals of his laboratory were to identify mechanisms of lung metastasis in bladder cancer that would lead to finding gene alterations responsible and then target these therapeutically. T24T metastatic bladder cancer cells were established from lung metastases and microarray was performed to yield 234 candidate metastasis tumor suppressor genes. To filter the 234 genes for significance, the expression level as a function of stage and grade in bladder cancer tissue was performed for the genes and resulted in the identification of RhoGDI2. RhoGDI2 is involved in the small GTPase signaling cascade that is involved in tumor cell growth, migration and metastasis. RhoGDI2 stains by immunohistochemistry in advanced and metastatic human bladder cancer tissue. Cells were transfected with RhoGDI2 and genes that were up- and down-regulated were noted. Endothelin-1 and neuromedin were significantly altered. Mice bearing T24T-GDI2 tumors were treated with Atrasentan (the endothelin-1 inhibitor) showed significant tumor inhibition. As a result, Atrasentan is being tested in the clinical setting for stages pT3-4N0-2 bladder cancer. Patients will receive chemotherapy, and then undergo randomization to placebo or Atrasentan.

Dr. Hong Wu, UCLA, presented data on PTEN and its role in CaP. PTEN regulates cell cycle and cell death pathways. Microarray was used to identify alterations in a model of PTEN induced CaP. This was done using mRNA for the transcriptome and protein for the proteome. These were then correlated for pathologic and pathway "signatures". For example, NKX3.1 was almost completed absent when PTEN is altered. When AKT is activated, NKX3.1 is also absent. This approach has then led to functional characterization of these alterations. Dr. Wu showed that NKX3.1 overexpression results in decreased cell proliferation and increased cell death. NKX3.1 overexpression then was noted to down-regulate phospho-AKT and serve as a negative regulator for androgen receptor expression. In summary, PTEN deletion leads to NKX3.1 down-regulation and up-regulation of AR thereby promoting CaP progression. NKX3.1 may be a good target for therapy.

Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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