Trastuzumab

McKeage, Kate; Perry, Caroline M.

doi:10.2165/00003495-200262010-00008

Cited by 249 publications

(79 citation statements)

References 33 publications

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“…As a corollary, our study strongly suggests to not only treat HER2/Neu-positive breast cancer patients with trastuzumab, an anti-HER2/Neu antibody delaying disease progression (64,65), but to additionally inhibit ACTR and/or the PEA3 subfamily of ETS proteins with yet-to-be developed strategies to enhance therapeutic effectiveness.…”

Section: Discussionmentioning

confidence: 78%

Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu

Goel

Janknecht

2004

Journal of Biological Chemistry

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Activator of thyroid and retinoic acid receptor (ACTR) is overexpressed in ϳ60% of primary human breast tumors and belongs to the p160 steroid receptor coactivator family. In this study, we identified a novel interaction partner of ACTR, the ETS transcription factor ER81 that is also heavily implicated in mammary tumor formation. ACTR and related p160 family members (steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein-1 (GRIP-1)) augment ER81-mediated transcription. Although ACTR and GRIP-1 can acetylate ER81, this posttranslational modification of ER81 is not required for its stimulation by ACTR or GRIP-1. In addition, ACTR collaborates with the p300 coactivator, a joint interaction partner of ACTR and ER81, to stimulate ER81 function and the ability of p300 to acetylate ER81 is indispensable for this collaboration. Furthermore, the receptor tyrosine kinase HER2/Neu, an oncoprotein particularly found overexpressed in breast tumors, cooperates with both ACTR and p300 to stimulate ER81-mediated transcription. Thus, oncogenic HER2/Neu and ACTR may synergize to orchestrate mammary tumorigenesis through the dysregulation of the transcription factor ER81 and its target genes.The p160 steroid receptor coactivator (SRC) 1 family gained much attention as pivotal coactivators for nuclear hormone receptors. Not only do SRCs interact with nuclear hormone receptors, they also facilitate the recruitment of other coactivators including the acetyltransferases CBP, p300, and P/CAF and the arginine methyltransferases CARM1 and PRMT1. Additionally, SRCs may acetylate histones on their own, all of which promotes transcription of nuclear hormone receptor target genes (1, 2). Three homologous members of the SRC coactivator family exist: SRC-1/NCoA-1 (nuclear coactivator-1); SRC-2/NCoA-2/TIF-2 (transcriptional intermediary factor-2)/ GRIP-1; and SRC-3/ACTR. ACTR has also been called p300/ CBP cointegrator-associated protein (p/CIP), receptor-associated coactivator-3 (RAC-3), amplified in breast cancer 1 (AIB1), and thyroid hormone receptor activator molecule-1 (TRAM-1) (3-8). Knock-out studies of ACTR have indicated that this coactivator has unique physiological functions that all relate to steroid and thyroid hormone action such as mammary gland development, female reproductive function, puberty, and somatic growth (9 -11).Recent studies have uncovered that the function of SRCs is not restricted toward nuclear hormone receptors but that they also regulate other transcription factors like MEF-2C (12), TEF-4 (13), AP-1 (14), serum response factor (15), nuclear factor B (16), STATs (5), and p53 (17). Moreover, ACTR mRNA has been shown to be overexpressed in ϳ60% of primary human breast tumors, which is the result of transcriptional up-regulation or gene amplification (7, 18 -20). Similarly, amplification and up-regulation of the ACTR gene were observed in ovarian, pancreatic, and gastric cancers (7,21,22). These studies suggest that ACTR overexpression may pleiotropically contribute to tumor formation, especi...

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Section: Discussionmentioning

confidence: 78%

Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu

Goel

Janknecht

2004

Journal of Biological Chemistry

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“…Overexpression of HER-2/neu receptor and/or amplification of the HER-2 gene has been identified in 20-30% of BC and it is associated with more aggressive disease and worse prognosis [3][4][5][6]. Targeting HER-2/neu with trastuzumab, a humanized anti HER-2/neu monoclonal antibody, inhibits the growth signals mediated by this oncogene [7]. Trastuzumab demonstrated moderate activity as single agent, but showed high activity in combination with chemotherapy as front-line therapy in HER-2/neu positive BC [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

Gasparini

Gion²,

Mariani³

et al. 2006

Breast Cancer Res Treat

129

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Background A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2. Patients and methods Among 124 patients randomized, 123 are assessable for toxicity and 118 for response. Patients received weekly paclitaxel single agent (80 mg/m 2 ) or combined with trastuzumab (4 mg/kg loading dose, then weekly 2 mg/kg). HER-2 overexpression was determined by immunohistochemistry (IHC). Patients with 2+/3+ IHC scores were eligible. IHC was compared with HER-2 serum extracellular domain (ECD). Results Patient characteristics were similar in the two arms. Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity. No patient developed cardiac toxicity. The combined treatment was statistically significant superior for overall response rate (ORR) (75% vs. 56.9%; P = 0.037), particularly in the subset of IHC 3+ patients (84.5% vs. 47.5%; P = 0.00050). A statistically significant better median time to progression was seen in the subgroup with IHC 3+ (369 vs. 272 days; P = 0.030) and visceral disease (301 vs. 183 days; P = 0.0080) treated with combination. Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR (P = 0.0035). Conclusion Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3+.

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“…Furthermore, tumor amplification of the HER-2 gene has been associated with resistance to a variety of chemotherapeutic agents and tamoxifen (3,4). Trastuzumab is a humanized monoclonal antibody with high specificity for the HER-2 protein (5), which demonstrated activity when used as a single agent in the first-or second-line treatment of metastatic breast cancer (MBC) (6,7) and in combination with chemotherapy (8)(9)(10). In a randomized controlled trial of first-line trastuzumab plus chemotherapy in women with HER-2/neu-positive MBC, the combination of trastuzumab and chemotherapy significantly improved time to progression, overall response rate, duration of response and overall survival compared with chemotherapy alone (11).…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer

Morabito,

Longo,

Gattuso

et al. 2006

Oncol Rep

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Abstract. The aim of this study was to evaluate the safety and efficacy of combined treatment with trastuzumab (T), gemcitabine (gem) and vinorelbine (vin) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab. Eligible patients had HER-2/neu-positive disease (IHC 2+ or 3+), performance status (PS) ≤2 and normal L-VEF. Patients were treated with weekly T (4 mg/kg on day 0, then 2 mg/kg), in combination with gem (800 mg/m 2 ) and vin (25 mg/m 2 ) on days 1 and 8, every 21 days. Patients were restaged every 3 cycles. A total of 30 patients (median age, 58 years; range, 41-74) were enrolled in the study. Fifteen patients were HER-2 3+ and 26 (86.7%) presented ≥2 metastatic sites. Of the patients, 7 (23.3%) had received trastuzumab as first-line therapy. Treatment was welltolerated with grade 4 neutropenia in 6 patients, grade 3 thrombocytopenia and grade 3 anemia in 1 patient, and grade 3 asthenia in 4 patients. Fifteen patients obtained an objective response (response rate, 50%; C.I. 95%, range, 31.3-68.7%). Among the patients with HER-2/neu 3+, the response rate was 73.3%. Noteworthy were 4 objective responses observed in patients with brain metastasis. Also, 7 patients had stable disease (23.3%). Median progression-free survival was 7 months (range 5-10), and median overall survival was 15 months (range 5-33). T-gem-vin is a safe and active regimen in this subgroup of patients with poor prognosis, and the efficacy of such a schedule was particularly satisfactory in patients with HercepTest 3+.

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Trastuzumab

Cited by 249 publications

References 33 publications

Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu

Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer

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