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View the Table of Contents for the December 1 issue of Molecular Cancer Therapeutics
Serrels et al. Page 3014
Elevated Src expression correlates with malignant potential and is also associated with metastatic disease, most notably in colon cancer. Dasatinib (BMS-354825) is a novel, orally active, multi-targeted kinase inhibitor that targets Src family kinases and is currently under clinical evaluation for the treatment of solid tumors. However, the effects of dasatinib on epithelial tumors are not fully understood. Serrels et al. found that colon carcinoma-bearing mice treated with dasatinib show a decrease in both phospho-Src Tyr419 and phospho-paxillin Tyr118 in peripheral blood mononuclear cells (PBMCs) that correlates with inhibition of Src activity in the colon tumors. Thus, PBMCs may provide a useful surrogate tissue for biomarker studies with dasatinib using inhibition of Src Tyr419 and paxillin Tyr118 phosphorylation as read-outs of Src activity.
Cardoso et al. Page 3042
Preclinical and clinical studies show that the proteasome inhibitor Bortezomib (PS341, VELCADE™) is highly effective when combined with chemotherapeutic agents. The value of Trastuzumab (Herceptin®) in HER-2 positive (IHC 3+ or FISH+) breast cancer is also known; however, the response rate is less than 40% for metastatic breast cancer. Cardoso et al. demonstrate that HER-2 positive and negative breast cancer cell lines’ susceptibility to Bortezomib is linked to NF-κB activity and p27 localization and that a strong correlation exists between HER-2 overexpression and constitutive NF-κB activation as well as p27 nuclear scarcity. In HER-2++/+++ cells, the Trastuzumab-Bortezomib combination has a strong effect on apoptosis or cytotoxicity in vitro, depending on the drug delivery protocol. This effect is higher than the addition of the effects of both drugs individually and could result from both drugs targeting NF-κB and p27, two proteins whose function and localization are closely linked with HER-2 overexpression. The authors are currently evaluating the potential clinical application of this drug combination in a phase 1 clinical trial.
Page 3232
The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a multifunctional agent with potent anti-inflammatory, anti-proliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. CDDO-Imidazolide is under active consideration for clinical development. Using both cell-free and cellular assays, Yore et al. show that CDDO-Im is a direct inhibitor of IκB kinase-β (IKKβ), and that it thereby inhibits binding of nuclear factor-κB (NF-κB) to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IκBα phosphorylation and degradation in response to tumor necrosis factor α (TNFα). The kinetics of this inhibition by CDDO-Im are rapid, occurring with 15 minutes. A biotinylated analog of CDDO-Im shows that CDDO-Im binds to the IKK signalsome. Furthermore, the authors show that cysteine 179 on IKK is a target for CDDO-Im. The authors also demonstrate that IκB kinase, a critical regulator of NF-κB, is a molecular target of CDDO-Imidazolide.