ANAHEIM, CA (UroToday.com) - Dr. Dan Theodorescu, University of Virginia presented “Ral GTPases and Friends: New Conspirators in Bladder Cancer Metastasis and Targets for Therapy” in the session “Target Selection in Renal Cell Carcinoma and Bladder Cancer”.

Dr. Theodorescu discussed novel therapies for metastatic bladder cancer (TCC). They developed a T24 metastatic model with a subtype T24T showing in vivo metastasis while the T24 does not. Using gene Chip technology, 412 candidate metastasis promoting genes were identified. They used human primary tumors and found 451 upregulated genes. Crossing this with the genes from the animal model, 14 common genes were found.

Ral-A is a small GTPase downstream of EFGR, PI3K and RAs. It can be activated by Aurora-A and is involved in facilitating cell migration. It is activated at the protein level as well. Ral-B was not found to be upregulated in primary tumors and its protein upregulation was not associated with tumor stage, but did correlate with metastasis. Ral-B expressing tumors grew better in mice and demonstrated that knockdown of Ral-B decreased in vitro cell migration in the Boyden chamber. Metastatic disease is significantly greater in animals growing Ral-B bladder tumors. Ral-A and Ral-B were downregulated either alone or together and the genes affected by this were identified. Nine genes were identified as being significant, of which CD24 was most interesting.

CD24 is important in cell anchorage and interacts with Src, FAK and other signaling molecules. In human TCC, IHC for CD24 correlated independently as a prognostic variable. In vitro, CD24 knockdowns have decreased growth and a monoclonal antibody against CD24 is demonstrating decreased growth and metastasis in preliminary mice studies.

Ral-B, but not Ral-A is a lung metastasis promoter gene and Ral-B regulates CD24 expression. CD24 is related to human TCC metastasis and is an independent prognostic marker for TCC survival post cystectomy. Ral-B is a potential therapeutic target.

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

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