Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha-particle emitting [213Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.
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PMID:Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate. 1503 48

Exemestane, a non-steroidal aromatase inhibitor that shuts down estrogen synthesis, and paclitaxel, an antineoplastic drug, inhibiting microtubule formation and interfering with the cells potential to proliferate, are well established treatments for metastatic breast cancer. Given that exemestane is a treatment for hormone-sensitive tumors in postmenopausal women with more favorable prognosis, while paclitaxel is normally used for women suffering from hormone-insensitive breast cancers with less favorable prognoses, there is currently no experience with the combination of the two drugs. In order to find out to what extent exemestane and paclitaxel add to each other's effects when given concomitantly, the effect of the two drugs alone and in combination on the growth of various gynecological tumor cell lines was assessed. Tumor cell growth was measured according to the cell titer cell proliferation technique, also referred to as the MTS assay, by measurement of relative cell numbers. In gynecological cancer cells expressing aromatase, the effect of a treatment with paclitaxel (10 nM) on cell growth was enhanced by co-treatment with exemestane. This additive effect was independent of ERalpha expression, but dependent on the presence of androstenedione. It was observed in HEC-1A and Ishikawa endometrial adenocarcinoma cells as well as in SK-OV-3 ovarian cancer and in MDA-MB-231 breast cancer cells. Our findings suggest that a combination of paclitaxel with exemestane might be beneficial for the treatment of aromatase-positive gynecological cancer, because it may allow us to reduce the paclitaxel dosage and therefore the toxicity of the treatment.
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PMID:Effects of a combination of exemestane and paclitaxel on human tumor cells in vitro. 1509 Jul 44

HER2 is the target of a new treatment for metastatic breast cancer using the humanized monoclonal antibody (MAb) trastuzumb (Herceptin). A novel alpha-particle emitting (213)Bi-Herceptin construct, targeting the HER2 extracellular domain on breast cancer cells, was produced by chelation and characterized in vitro in this study. We used Western blot and flow cytometry analysis to examine the expression of HER2 in a panel of established human metastatic breast cancer cell lines (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) MTS assay to evaluate the cytotoxicity and the TUNEL assay to analyze cellular apoptosis. Our results demonstrate that the human breast cancer cell lines BT-474 and SK-BR-3 express high levels of HER2 protein while MDA-231 expresses low levels of HER2. (213)Bi-Herceptin alpha conjugate (AC) was specifically cytotoxic to these cell lines in a HER2 level-dependent fashion, resulting in the cellular death through apoptosis. These results suggest that (231)Bi-Herceptin AC could be a novel agent for the treatment of breast cancer cell clusters or micro-metastases with high levels of HER2 expression.
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PMID:Cytotoxicity of breast cancer cells overexpressing HER2/neu by 213Bi-Herceptin radioimmunoconjugate. 1567 Aug 95

Roche Holding AG, and its subsidiaries Genentech Inc and Chugai Pharmaceutical Co Ltd, are developing trastuzumab emtansine (trastuzumab-DM1) for the treatment of HER2+ metastatic breast cancer. Trastuzumab emtansine is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc's cytotoxic and antimitotic maytansine derivative DM1. The maytansinoids bind microtubules in a manner similar to the vinca alkaloids; however, maytansinoids have been recognized to be 20- to 100-fold more potent at blocking mitosis. Nevertheless, the use of these compounds as single agents is limited by toxicity. By conjugating DM1 with trastuzumab, the delivery of the cytotoxic agent to target cells is more specific and reduces the safety concerns. In preclinical studies, the conjugation was effective in breast cancer cell lines resistant to trastuzumab, and demonstrated complete tumor regression in SCID mice bearing KPL4 breast cancer xenografts. Clinically, trastuzumab emtansine exhibited efficacy in patients with HER2+ metastatic breast cancer who had progressed on previous chemotherapy regimens or with trastuzumab therapy. Furthermore, preclinical studies have reported that trastuzumab emtansine potentiates the effect of a number of chemotherapeutic agents (including carboplatin, 5-fluorouracil and docetaxel), other antibodies, receptor tyrosine kinase inhibitors and PI3K inhibitors, and many of these combinations are set to be tested in humans. Trastuzumab emtansine offers an exciting new option for the treatment of patients with refractory, metastatic breast cancer.
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PMID:Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer. 2052 Dec 24

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.
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PMID:Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. 2200 71

The success of endocrine therapies for hormone receptor-positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 (HER2)-positive tumors has paved the way for the clinical development of several other metastatic breast cancer (MBC)-targeted therapies. Although the benefit of the anti-VEGF (vascular endothelial growth factor) monoclonal antibody bevacizumab in the MBC setting has become a topic of debate, clinical trial results are accumulating, and phase 3 evaluations are ongoing for newer HER2-targeted agents (pertuzumab and trastuzumab-maytansine immunoconjugate) and VEGF-targeted agents (aflibercept), as well as dual, epidermal growth factor receptor/HER2-targeted agents (afatinib [BIBW 2992] and neratinib), multitargeted tyrosine kinase inhibitors (sunitinib and pazopanib), and mammalian target of rapamycin (everolimus) and poly (ADP-ribose) polymerase 1 inhibitors (iniparib, olaparib). These agents as well as other novel classes of anticancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population.
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PMID:Current and emerging targeted therapies for metastatic breast cancer. 2200 69

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
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PMID:Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer. 2247 66

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.
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PMID:The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies. 2294 6

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.
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PMID:Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. 2319 84

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) which associates the selective intracellular targeting of the cytotoxic agent, DM1 (maytansine derivative) to the antitumor activity of trastuzumab. T-DM1 targets the epidermal growth factor receptor 2 (HER2), highly expressed in the most aggressive forms of breast cancer. Current standard of care in HER2-positive advanced or metastatic breast cancers has its limitations, particularly after progression on HER2-targeted approved therapies. T-DM1 showed a significant antitumor activity in vitro and in vivo, and in experimental models resistant to HER2-targeted agents. Phase I and II studies showed that the maximum tolerated dose for T-DM1 is 3.6 mg/kg given intravenously every three weeks. At this recommended dose, T-DM1 provided objective tumor responses and favourable safety profile. A phase II randomised study, evaluating T-DM1 in first line vs trastuzumab plus docetaxel, the current standard of care in advanced or metastatic breast cancers, showed improved tolerability and efficacy. Recently, the results of EMILIA, a phase III randomised study assessing, after prior treatment with trastuzumab and a taxane, the efficacy and the safety of T-DM1 vs lapatinib plus capecitabine, confirmed the therapeutic benefit. T-DM1 appears to be an effective therapeutic option to treat patients with HER2-positive metastatic breast cancer.
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PMID:[Antibody-drug conjugates in oncology: from the concept to trastuzumab emtansine (T-DM1)]. 2324 98


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