ANAHEIM, CA (UroToday.com) - Dr. Othon Iliopoulos, Harvard Medical School presented “VHL, Hypoxia-Dependent Pathways and VEGF in Renal Cell Carcinoma” in the session “Target Selection in Renal Cell Carcinoma and Bladder Cancer”.

Dr. Iliopoulos discussed the VHL-HIF signaling pathway in renal cell carcinoma (RCC). The histologic types of RCC have different biologic behavior. VHL is involved in clear cell carcinoma. Sporadic clear cell RCC has mutations in the VHL gene in 50% and promoter methylation in 20%. There are no VHL mutations in other RCC histologic types. VHL has a “gatekeeper” function and its restoration is sufficient for tumor suppression in mice. Hypoxia inducible factor (HIF) is a critical target of VHL. HIF-α is a transcriptional factor that is normally bound to VHL and inactivates it. VHL null cells constitutively express HIF and results in gene transactivation. VEGF, PDGF-beta and TGF-α are three of the main genes regulated by HIF and they promote cell proliferation, angiogenesis and along with E-cadherin regulate metastasis. Animal models of RCC tumors in which VHL bind to HIF do not demonstrate RCC. However, work demonstrates that HIF inhibition alone is sufficient to decrease RCC tumor formation. Inhibition of downstream HIF proteins such as VEFG, PDGF and TGF-α by sorafenib, sunitinib, bevacizumab, and tarceva for example are the basis for current treatment of metastatic RCC. Inhibition of HIF directly is another strategy using PI3K inhibitors, rapamycin, tarsolimus, temsirolimus and 17A-Geldanamycin. Combination therapy is also an approach.

Ongoing work includes identification of genes and chemicals that modulate HIF activity, novel and other critical HIF targets, finding second hits in RCC progression, mechanisms of resistance and biomarkers for RCC activity. Based upon the HIF signaling pathway, promoter regions that activate HIF were identified and tested with compounds that inactivate HIF. By gene expression profiling, these identified compounds do not globally inhibit other genes, thus demonstrating specificity. He pointed out that the signaling pathway in humans and Drosophila are similar and mutations in the fly can be used to identify genes altered by these mutations. The approach is signal dependent and organ restrictive, and markers are being validated in matched tumor and normal tissues. Plasma CA9 levels are an example of such work, as used to correlate tumor volume and outcomes.

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