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11-14-2005, 09:46 PM

Heard about this at a conference on Targeted Therapies in July

Here is an article from ASCO in May:
Meeting: 2005 ASCO Annual Meeting
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Category: Breast Cancer
SubCategory: Other

Ixabepilone (BMS-247550) plus trastuzumab combination chemotherapy induces synergistic antitumor efficacy in HER2 dependent breast cancers and is accompanied by modulation of molecular response markers
Abstract No: 561
Author(s): F. Y. Lee, S. Castaneda, I. Inigo, D. Kan, B. Paul, M. Wen, C. Fairchild, E. Clark, H. Lee
Abstract: Background: Ixabepilone (Ixa) belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Ixa is non-cross-resistant with the taxanes in preclinical human primary tumor models. In Phase II trials Ixa exhibited robust activities in breast cancers, with or without prior taxanes. Here we determined the activity of combined treatment with Ixa plus trastuzumab in preclinical breast cancer models, and identified potential pharmacogenomic correlates that predict responsiveness to the trastuzumab/Ixa combination Methods: BT474 and KPL-4 human breast cancer cell lines were used; both express the receptor tyrosine kinase HER2 and are dependent on HER2 signalling for growth. Effects of drug treatments in vitro were determined by a vital dye uptake assay (MTS) or a colony formation assay. In vivo, BT474 and KPL4 were grown as SC tumors in mice. Gene expression profiling was performed using the Affymetrix HG-U133 arrays Results: In cell culture, trastuzumab was cytostatic and inhibited the proliferation of BT474 and KPL-4 in a dose-dependent manner from 0.1-5 ?g/mL. Ixa in contrast was cytotoxic to both BT474 and KPL-4 cells with IC50s of 13.7 and 9.2 nM, respectively. Co-treatment of BT474 and KPL-4 cells with trastuzumab plus Ixa augmented the cytotoxic potency by more than 2-fold over Ixa alone (P<0.05). Treatment of KPL-4 tumored mice (n=8/group) with trastuzumab plus Ixa produced synergistic therapeutic effects. Trastuzumab treatment alone (10 mg/kg) produced no complete (CR) or partial (PR) response. Ixabepilone alone at its MTD (4 mg/kg) yielded 1 PR, 1 CR. The combined regimen produced 8 CR (4 of which were cured). Gene expression profiling revealed that trastuzumab treatment modulated the expression of several predictive marker genes, including the down-regulation of microtubule-associated proteins, tau Conclusions: Trastuzumab and Ixabepilone combination produced therapeutic synergism, which may be explained by changes in expression of predictive gene markers of drug response

11-14-2005, 09:46 PM	#5
Lani Guest Posts: n/a	Ixabepilone Heard about this at a conference on Targeted Therapies in July Here is an article from ASCO in May: Meeting: 2005 ASCO Annual Meeting Printer Friendly Bookmark Category: Breast Cancer SubCategory: Other Ixabepilone (BMS-247550) plus trastuzumab combination chemotherapy induces synergistic antitumor efficacy in HER2 dependent breast cancers and is accompanied by modulation of molecular response markers Abstract No: 561 Author(s): F. Y. Lee, S. Castaneda, I. Inigo, D. Kan, B. Paul, M. Wen, C. Fairchild, E. Clark, H. Lee Abstract: Background: Ixabepilone (Ixa) belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Ixa is non-cross-resistant with the taxanes in preclinical human primary tumor models. In Phase II trials Ixa exhibited robust activities in breast cancers, with or without prior taxanes. Here we determined the activity of combined treatment with Ixa plus trastuzumab in preclinical breast cancer models, and identified potential pharmacogenomic correlates that predict responsiveness to the trastuzumab/Ixa combination Methods: BT474 and KPL-4 human breast cancer cell lines were used; both express the receptor tyrosine kinase HER2 and are dependent on HER2 signalling for growth. Effects of drug treatments in vitro were determined by a vital dye uptake assay (MTS) or a colony formation assay. In vivo, BT474 and KPL4 were grown as SC tumors in mice. Gene expression profiling was performed using the Affymetrix HG-U133 arrays Results: In cell culture, trastuzumab was cytostatic and inhibited the proliferation of BT474 and KPL-4 in a dose-dependent manner from 0.1-5 ?g/mL. Ixa in contrast was cytotoxic to both BT474 and KPL-4 cells with IC50s of 13.7 and 9.2 nM, respectively. Co-treatment of BT474 and KPL-4 cells with trastuzumab plus Ixa augmented the cytotoxic potency by more than 2-fold over Ixa alone (P<0.05). Treatment of KPL-4 tumored mice (n=8/group) with trastuzumab plus Ixa produced synergistic therapeutic effects. Trastuzumab treatment alone (10 mg/kg) produced no complete (CR) or partial (PR) response. Ixabepilone alone at its MTD (4 mg/kg) yielded 1 PR, 1 CR. The combined regimen produced 8 CR (4 of which were cured). Gene expression profiling revealed that trastuzumab treatment modulated the expression of several predictive marker genes, including the down-regulation of microtubule-associated proteins, tau Conclusions: Trastuzumab and Ixabepilone combination produced therapeutic synergism, which may be explained by changes in expression of predictive gene markers of drug response