Dr. Gleave discussed "Targeted Therapies Update in Prostate Cancer". Clusterin, a chapparone protein is shown to have increased expression in advanced CaP and increases with androgen withdrawal. Clusterin inhibits protein aggregation, inhibits Bax and correlates with increased NK B activity. A second-generation anti-sense oligonucleotide against clusterin resulted in inhibition of CaP growth and progression in pre-clinical models. This therapy also enhances taxane and mitoxantrone tumor sensitivity. This combination of chemotherapy and anti-clusterin is now undergoing clinical trials in Canada. Dr. Gleave discussed that the clusterin drug must inhibit the pro-survival gene and resulting splice variants to be maximally effective. The clusterin clinical trials are also ongoing as Phase II in breast cancer.

Dr. Uzzo discussed "Targeted Therapies Update in Kidney Cancer". Numerous tumor suppressor genes have led to targeted therapies based upon gene-altered mechanisms. Hydroxylation of HIF1- results in upregulation of genes that promote renal cell cancer. New targeted therapies include therapies against VEGF, EGFR, PDGFR, cRaf, cKit and mTOR. Bevacizumab (anti-VEGF) increased median progression free survival, but no overall improvement in survival was found in clinical trials. Sorafenib is an oral receptor tyrosine kinase inhibitor against cRaf. It was approved December 2005. Median PFS was doubled from 12 to 24 weeks. Overall survival endpoint has not yet been reached. Tumor responses by imaging are impressive with Sorafenib. 12% of treated patients require dose reduction due to toxicity. Sunitinib is an oral inhibitor against receptor tyrosine kinases that regulate angiogenesis. It showed 35-43% overall response rates. Adverse events were moderate. MTOR inhibits rapamycin and CCI-779 is in clinical trials. It blocks the mTOR activation of HIF1- . Median time to progression was improved. These newly targeted therapies have led to the addition of at least 3 novel drugs for renal cell cancer within one year.

Dr. Dinney discussed "Targeted Therapies Update in Bladder Cancer". Targeted agents being studied are against EGFR, HER2, VEGF and muFGF3R. Most human urothelial cancers express EGFR and it correlates with increasing stage. Mutation of EGFR is shown to be important in response to therapy in lung cancer, but the gain of function mutations were not found in urothelial cancers. As such, EGFR inhibition is not too successful in bladder cancer. Analysis of pathways shows that redundancy permits bypassing the inhibition of EGFR. This had led to application inhibitors that are more effective against cell lines expression pathway signatures. At M.D. Anderson Cancer Center, a pre-cystectomy trial of Irresa will provide tissue for analysis of signaling pathways and confirm targets affected. This will lead to more specific patient selection for specific therapy with Irresa.

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

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