Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer

Ciardiello, Fortunato; Troiani, Teresa; Caputo, Francesca; Laurentiis, Michelino De; Palmieri, Giovannella; Vita, Ferdinando De; Diadema, Maria Rosaria; Orditura, Michele; Colantuoni, Giuseppe; Gridelli, Cesare; Catalano, Giuseppe; Placido, Sabino De; Bianco, Angelo Raffaele

doi:10.1038/sj.bjc.6603141

Cited by 77 publications

(46 citation statements)

References 43 publications

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“…Furthermore, there was significant preventive activity with Iressa in a Neu-driven ER À model of breast cancer in mice (26). However, a recent study in advanced tumors with Iressa plus the chemotherapeutic drug paclitaxel showed greater activity in ER + tumors (27). Thus, our strong efficacy in this ER + cancer model is not as surprising as might have been initially anticipated.…”

Section: Discussionmentioning

confidence: 67%

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

Lubet

Szabó

Christov

et al. 2008

Molecular Cancer Therapeutics

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The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studies, continual treatment with Iressa at 10, 3, or 1 mg/kg body weight per day beginning 5 days after MNU reduced tumor multiplicity by 93%, 43%, and 20%, respectively. Treatment of rats bearing small palpable cancers with Iressa (10 mg/kg body weight per day) resulted in the complete regression of 70% of the tumors. Short-term treatment of tumor-bearing rats with Iressa caused decreases in cell proliferation and phosphorylated epidermal growth factor receptor and increases in apoptosis. To examine treatment regimens that might decrease the skin toxicity associated with Iressa, both intermittent treatments and combinations of lower doses of Iressa with other effective agents were evaluated.

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Section: Discussionmentioning

confidence: 67%

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

Lubet

Szabó

Christov

et al. 2008

Molecular Cancer Therapeutics

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“…However, despite its significant potency against Her2-positive breast tumors, its efficacy in patients who express EGFRvIII with loss of PTEN function remains to be demonstrated. As a corollary to the great potency of trastuzumab, strategies are now being developed to enhance its potency in breast tumors using combinations with cytotoxic drugs (Ciardiello et al, 2006). Here, we describe a similar strategy based on the use of a small-molecule approach to target EGFR or Her2 TK-mediated signaling pathways while damaging DNA.…”

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confidence: 99%

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

Banerjee

Huang²,

McNamee³

et al. 2010

J Pharmacol Exp Ther

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Within the context of a new tumor-targeting strategy termed "combi-targeting," we designed RB24 to inhibit epidermal growth factor receptor (EGFR) or Her2 phosphorylation and to further degrade upon hydrolysis to 4-(3Ј-bromophenylamino)-6-aminoquinazoline (RB10; another EGFR/Her2 inhibitor) plus a strong DNA-alkylating species. 6-(3-Acetoxymethyl-3-methyltriazenyl)-4-(3Ј-bromophenylamino)quinazoline (RB24) showed significant antiproliferative activity against human breast cancer cells, and transfection of one such cell line, MDA-MB-435, with ErbB1 or ErbB2 (Her2) dramatically enhanced cell death by apoptosis. RB24 was capable of releasing 2-to 3-fold higher levels of RB10 in the transfectants than in their wild-type counterparts. More importantly, RB10 was abundantly distributed in the perinuclear region of the cells, and its elevated levels in the ErbB transfectants were concomitant with increased levels of DNA lesions in the latter cells. This selectivity could be abolished by coincubation of the cells with exogenous RB10, suggesting that the entire combi-molecule may bind primarily to its cognate perinuclear sites before degradation. This localization may exert a bystander effect, allowing the alkylating species to be abundantly propagated into the nucleus. Cell response to this novel targeting mechanism was mediated by 1) activation of c-Jun NH 2 -terminal kinase in response to DNA damage and 2) down-regulation of Bad through blockade of EGFR tyrosine kinase activity: two events that cooperatively converged into enhancement of apoptosis in the oncogene-transfected cells.Members of the epidermal growth factor (EGF) family of receptors, including EGFR, Her2 (ErbB2), and EGFRvIII (truncated EGFR), are overexpressed in 20 to 40% of breast cancers (Tang et al., 2000). The Her2 receptor, the closest EGFR homolog, is overexpressed in 20 to 25% of overall breast cancers, 60 to 70% of ductal carcinoma in situ, and is often associated with highly aggressive tumor phenotypes and poor disease-free survival (Slamon et al., 1989;Arteaga, 2001). For example, the average survival of breast cancer patients with Her2-positive tumors is 2 to 3 years compared with 6 to 7 years of Her2-negative tumors (Slamon et al., 1987;Borg et al., 1990). More importantly, this dysfunction is also associated with resistance to endocrine therapy and chemotherapy (Slamon et al., 1987). The significant implication of the ErbB family members in tumor progression has made them important targets for breast cancer therapy. Indeed, blockade of EGFR or Her2 has proven highly effective in breast xenograft models and in the clinic (Ciardiello et al., 1999; Molder et al., 2001). Although gefitinib (Iressa, ZD1839) that targets the EGFR tyrosine kinase (TK) has shown moderate activity in breast cancer models, trastuzumab (Herceptin), a monoclonal antibody directed toward Her2, has demonstrated significant activity in advanced

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“…Gefitnib has shown only limited benefit as a single agent in the treatment of metastatic breast cancer (6). However, trials of gefitinib in combination with trastuzumab or chemotherapy are being conducted (7,8). Preclinical studies also suggest synergistic effects of gefitinib in combination with hormonal agents (9).…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Inhibition Modulates the Nuclear Localization and Cytotoxicity of the Auger Electron Emitting Radiopharmaceutical 111In-DTPA Human Epidermal Growth Factor

Bailey

Costantini²,

Cai³

et al. 2007

Journal of Nuclear Medicine

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111 In-DTPA-human epidermal growth factor ( 111 In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of 111 In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. Methods: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 · 10 6 EGFRs/cell) in the presence or absence of 1 mM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with 111 In-DTPA-hEGF for 24 h at 37°C in the presence or absence of 1 mM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by 111 In were quantified using the g-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of 111 In-DTPA-hEGF alone or in combination with gefitinib. Results: Gefitinib (1 mM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanatelabeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized 111 In that localized in the nucleus was statistically significantly greater when 111 In-DTPA-hEGF was combined with gefitinib compared with 111 In-DTPA-hEGF alone (mean 6 SD: 26.0% 6 5.5% vs. 14.6% 6 4.0%, respectively; P , 0.05). Induction of g-H2AX foci was greater in MDA-MB-468 cells that were treated with 111 In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 mM) compared with those treated with 111 In-DTPA-hEGF alone (mean 6 SD: 35 6 4 vs. 24 6 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when 111 In-DTPA-hEGF (5 ng/mL, 6 MBq/mg) was combined with gefitinib (1 mM) compared with 111 In-DTPA-hEGF alone (42.9% 6 5.7% vs. 22.9% 6 3.6%, respectively; P , 0.01). Conclusion: The efficacy of 111 In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when 111 In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.

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Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer

Cited by 77 publications

References 43 publications

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

Epidermal Growth Factor Receptor Inhibition Modulates the Nuclear Localization and Cytotoxicity of the Auger Electron Emitting Radiopharmaceutical 111In-DTPA Human Epidermal Growth Factor

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