velcade(already FDA approved) and Herceptin synergistic --trial starting

[Lani]

1: Mol Cancer Ther. 2006 Dec 5; [Epub ahead of print] Links
Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.

Cardoso F,
Durbecq V,
Laes JF,
Badran B,
Lagneaux L,
Bex F,
Desmedt C,
Willard-Gallo K,
Ross JS,
Burny A,
Piccart M,
Sotiriou C.
Translational Research Unit and Laboratory of Experimental Hematology, Bordet Institute; Laboratoire de Microbiologie, Center for Education and Research in Food and Chemical Industry, Universite libre de Bruxelles, Brussels, Belgium; and Albany Medical College, Albany and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.
Background: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy. Methods: Drug cytotoxicity, both individually and together, and drug effects on p27 localization and NF-kappaB activation were investigated on four breast cancer cell lines: SKBR-3 (HER-2(+++)), MDA-MB-453 (HER-2(++)), HER-2-transfected MCF-7 (HER-2(+++)), and MCF-7 (HER-2(-)). Results: Bortezomib induced apoptosis in HER-2-positive and HER-2-negative breast cancer cells in a dose- and time-dependent manner. Together, these drugs induced apoptosis of HER-2(++/+++) cells at low concentrations, which had no effect when used alone, indicating there was a synergistic effect. Sequential treatment (trastuzumab then bortezomib) induced either necrosis or apoptosis, depending on the trastuzumab preincubation time. Susceptibility to bortezomib alone and the drug combination correlated with NF-kappaB activity and p27 localization. Conclusions: The addition of bortezomib to trastuzumab increases the effect of trastuzumab in HER-2(+++/++) cell lines in a synergistic way. This effect likely results from the ability of these two drugs to target the NF-kappaB and p27 pathways. The potential clinical application of this drug combination is under current evaluation by our group in a phase 1 clinical trial. [Mol Cancer Ther 2006;5(12):3042-51].
PMID: 17148762 [PubMed - as supplied by publisher]

[heblaj01]

Lani,
Can you clarify a point I do not understand even after reading the full text of the research paper (http://mct.aacrjournals.org/cgi/rapi...-06-0104v1.pdf).

Did the researchers prove that they overcame Herceptin resistance in the in vitro tests?
The reason I am not sure is that while they mention that one of the aim of the study was resistance, there is no clear indication that they used already resistant cancer cells. They appear to have selected low enough concentrations of Velcade & Herceptin to make them ineffective as single agents in treating the cells & then showed that combining the two low concentration drugs they achieved effective treatment.
Is that a correct understanding?