A total of 44C45 patients per arm did not receive any prior therapy

A total of 44C45 patients per arm did not receive any prior therapy. currently being tested in the neoadjuvant and adjuvant settings to identify patients who may Dihydroberberine benefit from this therapy. This review focuses on the mechanism of action, early and late-phase Rabbit Polyclonal to DDX55 clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer. strong class=”kwd-title” Keywords: T-DM1, trastuzumab emtansine, HER2-positive breast cancer, metastatic breast cancer, targeted therapies Introduction Breast cancer is one of the most frequent malignancies worldwide and represents an important public health problem.1 In the past years, the molecular understanding of this disease has shed light into its heterogeneity.2 The human epidermal growth factor receptor 2 (HER2) is Dihydroberberine a transmembrane receptor-like tyrosine kinase (RTK) overexpressed in 20%C25% of breast carcinomas.3 It is a member of the ErbB/EGFR receptor family that also encompasses EGFR/ErbB1, ErbB3, and ErbB4.4 Prior to the widespread use of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease, poor Dihydroberberine prognosis, and resistance to chemotherapeutic brokers.5 HER2 is the only member of the ErbB family that has no known ligand, and it is thought to be primarily the preferential heterodimerization partner for other ErbB receptors.6 In 2003, analysis of the crystal structure of HER2 revealed that this extracellular region of the receptor is in a fixed dimerization state, making it available to interact with any other ErbB RTK. This key observation led to a better understanding of the transforming capabilities of HER2 overexpression, with increasing availability to form hetero- or homodimers that lead to enhanced signaling in both the presence and absence of ligands.7 Trastuzumab, a humanized IgG1 monoclonal antibody directed against the extracellular domain name of HER2, was the first targeted therapy against HER2 to show clinical efficacy in breast cancer.8 Multiple mechanisms of action have been proposed, including PI3K/Akt and MAPK signaling inhibition, antibody-dependent cell-mediated cytotoxicity exerted by the immune system, prevention of HER2 cleavage by matrix metalloproteinases, and angiogenesis inhibition.9 While the combination of trastuzumab with chemotherapy is effective both in the advanced and the adjuvant settings, virtually all metastatic patients will eventually progress to therapy8 and a proportion of patients will develop recurrence after postoperative treatment,10 making de novo and acquired resistance an important clinical problem. Preclinical studies on trastuzumab resistance have proposed several mechanisms to explain this phenomenon. These include masking of HER2 epitopes by the membrane-bound mucin MUC-4,11 increased signaling through other ErbB receptors,12,13 activation of PI3K/Akt pathway by activating PIK3CA mutations and loss of PTEN,14C16 signaling through alternative RTK families such as IGF-1,17 and the expression of p95HER2 fragments that have lost variable portions of the extracellular domains and retain kinase activity.18,19 Trastuzumab emtansine (T-DM1) is one of the novel agents recently found to improve outcomes in HER2-positive breast cancer that is resistant to trastuzumab. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer. Mechanism of action T-DM1 is part of the antibody-drug conjugate (ADC) class of anticancer brokers that combine cytotoxic brokers with monoclonal antibodies as a means of enhancing drug delivery to specifically targeted cells. The key objective of this approach is to maximize efficacy while sparing toxicity to normal tissues. ADCs share three components: the antibody, a linker molecule, and the cytotoxic moiety. Specificity of conventional chemotherapy relies on the fact that highly proliferative cells are more sensitive to cytotoxic effects, but this implies considerable activity on normal cells, which results in significant toxicity and partially explains the narrow therapeutic window often seen with this kind of therapy. T-DM1 results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine, through a covalent bond, thus delivering highly effective chemotherapy to targeted cells and sparing unwanted adverse effects. Preclinical research identified a synergistic interaction.

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